Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof

ABSTRACT

The present invention relates to glucopyranosyl-oxybenzylbenzene derivatives represented by the general formula:  
                 
 
wherein R 1  represents a hydrogen atom, a hydroxy group, a substituted or unsubstituted amino group, a carbamoyl group, a substituted or unsubstituted(lower alkyl) group, a substituted or unsubstituted(lower alkoxy) group etc.; R 2  represents a hydrogen atom or a lower alkyl group; and R 3  represents a substituted or unsubstituted(lower alkyl) group, a substituted or unsubstituted(lower alkoxy) group, a substituted or unsubstituted(lower alkylthio) group etc., or pharmaceutically acceptable salts thereof, which have an inhibitory activity in human SGLT 2  and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, diabetic complication or obesity, pharmaceutical compositions comprising the same and intermediates thereof.

TECHNICAL FIELD

The present invention relates to glucopyranosyloxybenzylbenzenederivatives or pharmaceutically acceptable salts thereof, which areuseful as medicaments, pharmaceutical compositions comprising the sameand intermediates thereof.

More particularly, the present invention relates toglucopyranosyloxybenzylbenzene derivatives or pharmaceuticallyacceptable salts thereof, which have an inhibitory activity in humanSGLT2 and are useful as agents for the prevention or treatment of adisease associated with hyperglycemia such as diabetes, diabeticcomplication or obesity, pharmaceutical compositions comprising the sameand intermediates thereof.

BACKGROUND ART

Diabetes is one of lifestyle-related diseases with the background ofchange of eating habit and lack of exercise. Hence, diet and exercisetherapies are performed in patients with diabetes. Furthermore, when itssufficient control and continuous performance are difficult, drugtreatment is simultaneously performed. Now, biguanides, sulfonylureasand agents for reducing insulin resistance have been employed asantidiabetic agents. However, biguanides and sulfonylureas showoccasionally adverse effects such as lactic acidosis and hypoglysemia,respectively. In a case of using agents for reducing insulin resistance,adverse effects such as edema occasionally are observed, and it is alsoconcerned for advancing obesity. Therefore, in order to solve theseproblems, it has been desired to develop antidiabetic agents having anew mechanism.

In recent years, development of new type antidiabetic agents has beenprogressing, which promote urinary glucose excretion and lower bloodglucose level by preventing excess glucose reabsorption at the kidney(J. Clin. Invest., Vol. 79, pp. 1510-1515 (1987)). In addition, it isreported that SGLT2 (Na⁺/glucose cotransporter 2) is present in the S1segment of the kidney's proximal tubule and participates mainly inreabsorption of glucose filtrated through glomerular (J. Clin. Invest.,Vol. 93, pp. 397-404 (1994)). Accordingly, inhibiting a human SGLT2activity prevents reabsorption of excess glucose at the kidney,subsequently promotes excreting excess glucose though the urine, andnormalizes blood glucose level. Therefore, fast development ofantidiabetic agents, which have a potent inhibitory activity in humanSGLT2 and have a new mechanism, has been desired. Furthermore, sincesuch agents promote the excretion of excess glucose though the urine andconsequently the glucose accumulation in the body is decreased, they arealso expected to have a preventing effect on obesity.

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly to find compounds having aninhibitory activity in human SGLT2. As a result, it was found thatcertain glucopyranosyloxybenzylbenzene derivatives show an excellentinhibitory activity in human SGLT2 as mentioned below, thereby formingthe basis of the present invention.

The present invention is to provide the followingglucopyranosyloxybenzylbenzene derivatives and pharmaceuticallyacceptable salts thereof, which exert an inhibitory activity in humanSGLT2 and show an excellent hypoglycemic effect by excreting excessglucose in the urine through preventing the reabsorption of excessglucose at the kidney, and pharmaceutical compositions comprising thesame.

This is, the present invention relates to aglucopyranosyloxybenzylbenzene derivative represented by the generalformula:

wherein R¹ represents a hydrogen atom, a hydroxy group, an amino group,a mono or di(lower alkyl)amino group, a carbamoyl group, a lower alkylgroup, a lower alkoxy group, a hydroxy(lower alkyl) group, ahydroxy(lower alkoxy) group, a lower alkoxy-substituted (lower alkyl)group, a lower alkoxy-substituted (lower alkoxy) group, acarbamoyl(lower alkyl) group, a lower alkoxy-carbonyl-substituted (loweralkyl) group, a lower alkoxy-carbonyl-substituted (lower alkoxy) group,a carboxy(lower alkyl) group or a carboxy(lower alkoxy) group; R²represents a hydrogen atom or a lower alkyl group; and R³ represents alower alkyl group, a lower alkoxy group, a lower alkylthio group, ahydroxy(lower alkyl) group, a hydroxy(lower alkoxy) group, ahydroxy(lower alkylthio) group, a lower alkoxy-substituted (lower alkyl)group, a lower alkoxy-substituted (lower alkoxy) group, a loweralkoxy-substituted (lower alkylthio) group, a lower alkenyloxy group, anaralkyloxy group, a hydroxy(lower alkenyl) group, a carboxy group, alower alkoxycarbonyl group, a cyano group, an aralkyloxy(lower alkyl)group, a cyano(lower alkyl) group, a carbamoyl group, a carbamoyl(loweralkyl) group, an amino group, a mono or di(lower alkyl)amino group, alower alkoxycarbonyl-substituted (lower alkyl) group, a loweralkoxycarbonyl-substituted (lower alkoxy) group, a carboxy-(lower alkyl)group or a carboxy(lower alkoxy) group; with the proviso that R³ doesnot represent a lower alkyl group, a lower alkoxy group, a loweralkylthio group, a hydroxy(lower alkyl) group, a hydroxy(lower alkoxy)group, a hydroxy (lower alkylthio) group, a lower alkoxy-substituted(lower alkyl) group, a lower alkoxy-substituted (lower alkoxy) group ora lower alkoxy-substituted (lower alkylthio) group when R¹ represents ahydrogen atom or a hydroxy(lower alkyl) group and R² represents ahydrogen atom, or a pharmaceutically acceptable salt thereof.

The present invention relates to a pharmaceutical composition comprisingas an active ingredient a glucopyranosyloxybenzylbenzene derivativerepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof.

The present invention relates to a human SGLT2 inhibitor comprising asan active ingredient a glucopyranosyloxy-benzylbenzene derivativerepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof.

The present invention relates to an agent for the prevention ortreatment of a disease associated with hyperglycemia, which comprises asan active ingredient a glucopyranosyloxybenzylbenzene derivativerepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof.

The present invention relates to a method for the prevention ortreatment of a disease associated with hyperglycemia, which comprisesadministering an effect amount of a glucopyranosyloxybenzylbenzenederivative represented by the above general formula (I) or apharmaceutically acceptable salt thereof.

The present invention relates to a use of aglucopyranosyloxybenzylbenzene derivative represented by the abovegeneral formula (I) or a pharmaceutically acceptable salt thereof forthe manufacture of a pharmaceutical composition for the prevention ortreatment of a disease associated with hyperglycemia.

In addition, the present invention relates to a benzylphenol derivativerepresented by the general formula:

wherein R¹¹ represents a hydrogen atom, a protected hydroxy group, aprotected amino group, a protected mono(lower alkyl)amino group, adi(lower alkyl)amino group, a carbamoyl group, a lower alkyl group, alower alkoxy group, a protected hydroxy(lower alkyl) group, a protectedhydroxy(lower alkoxy) group, a lower alkoxy-substituted (lower alkyl)group, a lower alkoxy-substituted (lower alkoxy) group, a carbamoyl(lower alkyl) group, a lower alkoxycarbonyl-substituted (lower alkyl)group, a lower alkoxycarbonyl-substituted (lower alkoxy) group, acarboxy-(lower alkyl) group or a carboxy(lower alkoxy) group; R¹²represents a hydrogen atom or a lower alkyl group; and R¹³ represents alower alkyl group, a lower alkoxy group, a lower alkylthio group, aprotected hydroxy(lower alkyl) group, a protected hydroxy(lower alkoxy)group, a protected hydroxy-(lower alkylthio) group, a loweralkoxy-substituted (lower alkyl) group, a lower alkoxy-substituted(lower alkoxy) group, a lower alkoxy-substituted (lower alkylthio)group, a lower alkenyloxy group, an aralkyloxy group, a protectedhydroxy(lower alkenyl) group, a carboxy group, a lower alkoxycarbonylgroup, a cyano group, an aralkyloxy(lower alkyl) group, a cyano(loweralkyl) group, a carbamoyl group, a carbamoyl(lower alkyl) group, anprotected amino group, a protected mono(lower alkyl)amino group, adi(lower alkyl)amino group, a lower alkoxy-carbonyl-substituted (loweralkyl) group, a lower alkoxy-carbonyl-substituted (lower alkoxy) group,a carboxy(lower alkyl) group or a carboxy(lower alkoxy) group; with theproviso that R¹³ does not represent a lower alkyl group, a lower alkoxygroup, a lower alkylthio group, a protected hydroxy(lower alkyl) group,a protected hydroxy(lower alkoxy) group, a protected hydroxy(loweralkylthio) group, a lower alkoxy-substituted (lower alkyl) group, alower alkoxy-substituted (lower alkoxy) group or a loweralkoxy-substituted (lower alkylthio) group when R¹¹ represents ahydrogen atom or a protected hydroxy(lower alkyl) group and R¹²represents a hydrogen atom, or a salt thereof.

In the present invention, the term “lower alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “lower alkoxy group” means astraight-chained or branched alkoxy group having 1 to 6 carbon atomssuch as a methoxy group, an ethoxy group, a propoxy group, an isopropoxygroup, a butoxy group, an isobutoxy group, a sec-butoxy group, atert-butoxy group, a pentyloxy group, an isopentyloxy group, aneopentyloxy group, a tert-pentyloxy group, a hexyloxy group or thelike; and the term “lower alkylthio group” means a straight-chained orbranched alkylthio group having 1 to 6 carbon atoms such as a methylthiogroup, an ethylthio group, a propylthio group, an isopropylthio group, abutylthio group, an isobutylthio group, a sec-butylthio group, atert-butylthio group, a pentylthio group, an isopentylthio group, aneopentylthio group, a tert-pentylthio group, a hexylthio group or thelike. The term “hydroxy(lower alkyl) group” means a straight-chained orbranched hydroxyalkyl group having 1 to 6 carbon atoms such as ahydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxyethyl group, a3-hydroxypropyl group, a 2-hydroxypropyl group, a 1-hydroxypropyl group,a 2-hydroxy-1-methylethyl group, a 4-hydroxybutyl group, a3-hydroxybutyl group, a 2-hydroxybutyl group, a 1-hydroxybutyl group, a5-hydroxypentyl group, a 4-hydroxypentyl group, a 3-hydroxypentyl group,a 2-hydroxypentyl group, a 1-hydroxypentyl group, a 6-hydroxyhexylgroup, a 5-hydroxyhexyl group, a 4-hydroxyhexyl group, a 3-hydroxyhexylgroup, a 2-hydroxyhexyl group, a 1-hydroxyhexyl group or the like; theterm “hydroxy(lower alkoxy) group” means a straight-chained or branchedhydroxyalkoxy group having 2 to 6 carbon atoms such as a 2-hydroxyethoxygroup, a 3-hydroxypropoxy group, a 2-hydroxypropoxy group, a2-hydroxy-1-methylethoxy group, a 4-hydroxybutoxy group, a3-hydroxybutoxy group, a 2-hydroxybutoxy group, a 5-hydroxypentyloxygroup, a 4-hydroxypentyloxy group, a 3-hydroxypentyloxy group, a2-hydroxypentyloxy group, a 6-hydroxyhexyloxy group, a 5-hydroxyhexyloxygroup, a 4-hydroxyhexyloxy group, a 3-hydroxyhexyloxy group, a2-hydroxyhexyloxy group or the like; and the term “hydroxy(loweralkylthio) group” means a straight-chained or branched hydroxyalkylthiogroup having 2 to 6 carbon atoms such as an 2-hydroxyethylthio group, a3-hydroxypropylthio group, a 2-hydroxypropylthio group, a2-hydroxy-1-methylethylthio group, a 4-hydroxybutylthio group, a3-hydroxybutylthio group, a 2-hydroxybutylthio group, a5-hydroxypentylthio group, a 4-hydroxypentylthio group, a3-hydroxypentylthio group, a 2-hydroxypentylthio group, a6-hydroxyhexylthio group, a 5-hydroxyhexylthio group, a4-hydroxyhexylthio group, a 3-hydroxyhexylthio group, a2-hydroxyhexylthio group or the like. The term “lower alkoxy-substituted(lower alkyl) group” means the above lower alkyl group substituted bythe above lower alkoxy group; the term “lower alkoxy-substituted (loweralkoxy) group” means the above lower alkoxy group substituted by theabove lower alkoxy group; and the term “lower alkoxy-substituted (loweralkylthio) group” means the above lower alkylthio group substituted bythe above lower alkoxy group. The term “lower alkenyloxy group” astraight-chained or branched alkenyloxy group having 2 to 6 carbon atomssuch as an allyloxy group; the term “hydroxy(lower alkenyl) group” meansa straight-chained or branched hydroxy-alkenyl group having 3 to 6carbon atoms such as an 3-hydroxy-1-propenyl group; the term “aralkyloxygroup” means the above lower alkoxy group substituted by an aryl group(e.g., a phenyl group, a naphthyl group and the like) such as abenzyloxy group; the term “aralkyloxy(lower alkyl) group” means theabove lower alkyl group substituted by the above aralkyloxy group; theterm “cyano(lower alkyl) group” means the above lower alkyl groupsubstituted by a cyano group; the term “carbamoyl(lower alkyl) group”means the above lower alkyl group substituted by a carbamoyl group; and“mono or di (lower alkyl)amino group” means an amino group mono ordisubstituted by the above lower alkyl group. The term “loweralkoxycarbonyl group” means a straight-chained or branchedalkoxycarbonyl group having 2 to 7 carbon atoms such as amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,an isopropyloxycarbonyl group, a butoxycarbonyl group, anisobutyloxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group, a pentyloxycarbonyl group, anisopentyloxycarbonyl group, a neopentyloxycarbonyl group, atert-pentyloxycarbonyl group, a hexyloxycarbonyl group or the like; theterm “lower alkoxy-carbonyl-substituted (lower alkyl) group” means theabove lower alkyl group substituted by the above lower alkoxycarbonylgroup; the term “lower alkoxycarbonyl-substituted (lower alkoxy) group”means the above lower alkoxy group substituted by the above loweralkoxycarbonyl group; and the term “carboxy(lower alkyl) group” meansthe above lower alkyl group substituted by a carboxy group; and the term“carboxy(lower alkoxy) group means the above lower alkoxy groupsubstituted by a carboxy group.

The term “hydroxy-protective group” means a hydroxy-protective groupused in general organic reactions such as a benzyl group, amethoxymethyl group, an acetyl group, a benzoyl group or the like. Theterm “amino-protective group” means an amino-protective group used ingeneral organic reactions such as a benzyloxycarbonyl group, atert-butoxycarbonyl group, a phthaloyl group, a benzyl group, an acetylgroup or the like.

For example, the compounds represented by the above general formula (I)of the present invention can be prepared using a benzylphenol derivativerepresented by the above general formula (II) of the present inventionaccording the following procedure:

wherein X represents a leaving group such as a trichloro-acetoimidoyloxygroup, an acetoxy group, a bromine atom or a fluorine atom; and R¹, R²,R³, R¹¹, R¹² and R¹³ have the same meanings as defined above.Process 1

A glucoside represented by the above general formula (IV) can beprepared by subjecting a benzylphenol derivative represented by theabove general formula (II) or a salt thereof to glycosidation using aglycosyl-donor represented by the above general formula (III) such as2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose,2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-β-D-glucopyranose,1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose,2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide and2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl fluoride in the presence of anactivating reagent such as boron trifluoride-diethyl ether complex,silver trifluoromethanesulfonate, tin (IV) chloride or trimethylsilyltrifluoromethanesulfonate in an inert solvent. As the solvent used,dichloromethane, toluene, acetonitrile, nitromethane, ethylacetate,diethylether, chloroform, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from −30° C. to refluxtemperature, and the reaction time is usually from 10 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In addition, compounds wherein substituents R¹¹ and/or R¹³have a hydroxy-protective group or an amino-protective group can be usedin the process 2 after removing appropriately the protective group inthe usual way subsequent to reaction completion of this process.

Process 2

A compound (I) of the present invention can be prepared by subjecting aglucoside represented by the above general formula (IV) to alkalinehydrolysis to remove the hydroxy-protective groups. As the solvent used,water, methanol, ethanol, tetrahydrofuran, a mixed solvent thereof andthe like can be illustrated, and as alkaline materials, sodiumhydroxide, sodium methoxide, sodium ethoxide or the like can be used.The treatment temperature is usually from 0° C. to reflux temperature,and the treatment time is usually from 30 minutes to 6 hours, varyingbased on a used starting material, solvent and treatment temperature. Inaddition, compounds wherein substituents R¹¹ and/or R¹³ have ahydroxy-protective group or an amino-protective group can be carried outby modifying the above treatment method appropriately in the usual wayand can be derived into a desired compound (I) by removing theprotective group in the usual way subsequent to reaction completion ofthis process.

For example, of the compounds represented by the above general formula(I) of the present invention, compounds represented by the followinggeneral formula (Ia) can be also prepared using a carboxylic acidderivative represented by the above general formula (V) according thefollowing procedure:

wherein Y represents a straight-chained or branched alkyl group having 1to 5 carbon atoms or a straight-chained or branched alkenyl group having2 to 5 carbon atoms; R represents a hydrogen atom or a lower alkylgroup; and R¹ and R² have the same meanings as defined above.Process 3

A compound represented by the above general formula (Ia) can be preparedby subjecting a carboxylic acid derivative represented by the abovegeneral formula (V) to reduction using a reducing agent such as lithiumaluminium hydride, boran or lithium borohydride in a solvent such astetrahydrofuran, diethyl ether, methanol, ethanol or a mixed solventthereof. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Furthermore, for example, of the compounds represented by the abovegeneral formula (I) of the present invention, compounds represented bythe following general formula (Ib) can be also prepared using a phenolderivative represented by the above general formula (Ic) according thefollowing procedure:

wherein R⁴ represents a lower alkoxy group, a hydroxy(lower alkoxy)group, a lower alkoxy-substituted (lower alkoxy) group, a loweralkoxycarbonyl-substituted (lower alkoxy) group or a carboxy(loweralkoxy) group; R⁵ represents a lower alkyl group, a protectedhydroxy(lower alkyl) group, a lower alkoxy-substituted (lower alkyl)group or a lower alkoxycarbonyl-substituted (lower alkyl) group; X¹represents a leaving group such as a chlorine atom, a bromine atom, aniodine atom, a mesyloxy group or tosyloxy group; and R² and R³ have thesame meanings as defined above.Process 4

A compound represented by the above general formula (Ib) can be preparedby subjecting a phenol derivative represented by the above generalformula (Ic) to O-alkylation using an alkylating agent represented bythe above general formula (VI) in the presence of an alkaline materialsuch as sodium hydride, potassium carbonate, cesium carbonate, potassiumtert-butoxide, sodium hydroxide, potassium hydroxide or sodium hydrogencarbonate in a solvent such as tetrahydrofuran, N,N-dimethyl-formamide,dimethyl sulfoxide, acetonitrile or a mixed solvent thereof, andremoving the protective group in the usual way as occasion demands. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Of the compounds represented by the above general formula (IV),compounds wherein R¹¹ represents a protected mono(lower alkyl)aminogroup can be prepared by allowing a corresponding compound wherein R¹¹represents a protected amino group to react with an appropriatealkylating agent such as a lower alkyl halide, a mesylate compound or atosylate compound in the presence of an alkaline material such as sodiumhydride or potassium carbonate in a solvent such as tetrahydrofuran,N,N-dimethyl-formamide, dimethyl sulfoxide or a mixed solvent thereof.

For example, the compounds represented by the above general formula (II)of the present invention which are used as starting materials in theaforementioned production process and salts thereof can be preparedaccording to the following procedure:

wherein M represents hydrogen atom or a hydroxy-protective group; R⁶represents a hydrogen atom, a protected hydroxy group, a protected aminogroup, a protected mono (lower alkyl)amino group, a di(lower alkyl)aminogroup, a carbamoyl grop, a lower alkyl group, a lower alkoxy group, aprotected hydroxy(lower alkyl) group, a protected hydroxy(lower alkoxy)group, a lower alkoxy-substituted (lower alkyl) group, a loweralkoxy-substituted (lower alkoxy) group, a carbamoyl (lower alkyl)group, a lower alkoxycarbonyl-substituted (lower alkyl) group, a loweralkoxycarbonyl-substituted (lower alkoxy) group, a carboxy-(lower alkyl)group, a carboxy(lower alkoxy) group or a lower alkoxycarbonyl group;one of Y and Z represents MgBr, MgCl, MgI or a lithium atom, while theother represents a formyl group; and R¹¹, R¹² and R¹³ have the samemeanings as defined above.Process A

A compound represented by the above general formula (IX) can be preparedby condensing a benzaldehyde derivative represented by the above generalformula (VII) with a Grignard reagent or a lithium reagent representedby the above general formula (VIII), or by condensing a Grignard reagentor a lithium reagent represented by the above general formula (VII) witha benzaldehyde derivative represented by the above general formula(VIII) in an inert solvent. As the solvent used, tetrahydrofuran,diethyl ether, a mixed solvent thereof and the like can be illustrated.The reaction temperature is usually from −78° C. to reflux temperature,and the reaction time is usually from 10 minutes to 1 day, varying basedon a used starting material, solvent and reaction temperature.

Process B

A compound represented by the above general formula (X) can be preparedby subjecting a compound represented by the above general formula (IX)to oxidation using a Dess-Martin reagent in an inert solvent. As thesolvent used, dichloromethane, chloroform, acetonitrile, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from 0° C. to reflux temperature, and the reaction time isusually from 1 hour to 1 day, varying based on a used starting material,solvent and reaction temperature.

Process C

A compound represented by the above general formula (II) of the presentinvention can be prepared by removing the protective group of a compoundrepresented by the above general formula (X) in the usual way,condensing the resulting compound with methyl chloroformate in thepresence of a base such as triethylamine, diisopropylethylamine or4-(N,N-dimethyl-amino)pyridine in an inert solvent and subjecting theresulting carbonate compound to reduction using a reducing agent such assodium borohydride. As the solvent used in the condensing reaction,tetrahydrofuran, dichloromethane, acetonitrile, ethyl acetate, diethylether, a mixed solvent thereof and the like can be illustrated. Thereaction temperature is usually from 0° C. to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. As thesolvent used in the reducing reaction, a mixed solvent withtetrahydrofuran and water, and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 1 hour to 1 day, varying based on a usedstarting material, solvent and reaction temperature. In case that R⁶represents a lower alkoxycarbonyl group, the corresponding compounds canbe derived into the compound represented by the above general formula(II) of the present invention by reducing said group using a reducingagent such as lithium aluminium hydride in an inert solvent into ahydroxymethyl group and protecting the hydroxy group in the usual way.As the solvent used in the reducing reaction, diethyl ether,tetrahydrofuran, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 10 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In addition, the compounds represented by the above generalformula (II) of the present invention can be converted into a saltthereof such as a sodium salt or a potassium salt in the usual way.

Process D

A compound represented by the above general formula (II) of the presentinvention can be prepared by subjecting a compound represented by theabove general formula (IX) to catalytic hydrogenation using a palladiumcatalyst such as palladium-carbon in the presence or absence of an acidsuch as hydrochloric acid in an inert solvent, and removing orintroducing the protective group in the usual way as occasion demands.As the solvent used in the catalytic hydrogenation, methanol, ethanol,tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. In case thatR⁶ represents a lower alkoxycarbonyl group, the corresponding compoundscan be derived into the compound represented by the above generalformula (II) of the present invention by reducing said group using areducing agent such as lithium aluminium hydride in an inert solventinto a hydroxymethyl group and protecting the hydroxy group in the usualway. As the solvent used in the reducing reaction, diethyl ether,tetrahydrofuran, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 10 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In addition, the compound of the above general formula (II)of the present invention can be converted into a salt thereof such as asodium salt or a potassium salt in the usual way.

In the compounds represented by the above general formulae (II), (VII),(VIII), (IX) and (X), compounds wherein substituents R¹¹ and/or R¹³represent a carboxy group, an amino group, a cyano group, a carbamoylgroup, a hydroxy(lower alkyl) group, a carboxy(lower alkyl) group, acarboxy(lower alkenyl) group, a lower alkoxycarbonyl-substituted (loweralkyl) group, a lower alkoxycarbonyl-substituted (lower alkenyl) group,an amino(lower alkyl) group, a cyano(lower alkyl) group, acarbamoyl(lower alkyl) group or the like can be prepared by convertingappropriately from the corresponding compound having a loweralkoxycarbonyl group as a substituent in the usual way and can be usedin the subsequent processes (processes A-D and 1).

The compounds represented by the above general formula (II) of thepresent invention which are used as starting materials in theaforementioned production process and salts thereof can be also preparedaccording the following procedure:

wherein X² represents a leaving group such as a chlorine atom; and R¹¹,R¹² and R¹³ have the same meanings as defined above.Process E

A compound represented by the above general formula (II) can be preparedby subjecting a phenol derivative represented by the above generalformula (XI) to benzylation using a benzyl derivative represented by theabove general formula (XII) in the presence of an alkaline material suchas lithium hydroxide without any solvent. The reaction temperature isusually from 50 to 200° C., and the reaction time is usually from 30minutes to 1 day, varying based on a used starting material, solvent andreaction temperature.

The compounds of the present invention obtained by the above productionprocesses can be isolated and purified by conventional separation meanssuch as fractional recrystallization, purification using chromatography,solvent extraction and solid phase extraction.

The glucopyranosyloxybenzylbenzene derivatives represented by the abovegeneral formula (I) of the present invention can be converted into theirpharmaceutically acceptable salts in the usual way. Examples of the suchsalts include acid addition salts with mineral acids (e.g., hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid andthe like), acid addition salts with organic acids (e.g., acetic acid,adipic acid, citric acid, fumaric acid, maleic acid, oleic acid, lacticacid, stearic acid, succinic acid, tartaric acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like), salts withorganic amines (e.g., 2-aminoethanol, piperidine, morpholine,pyrrolidine and the like), and salts with inorganic base such as asodium salt, a potassium salt, a calcium salt or a magnesium salt.

The compounds represented by the above general formula (I) of thepresent invention include their hydrates and their solvates withpharmaceutically acceptable solvents such as ethanol.

Of the compounds represented by the above general formula (I) of thepresent invention, compounds having an unsaturated bond exist in twogeometrical isomer forms. Either cis(Z)-isomer or trans(E)-isomer can beemployed in the present invention.

Of the compounds represented by the above general formula (I) of thepresent invention, compounds having an asymmetric carbon atom with theexception of the glucopyranosyloxy moiety exist in two optical isomerforms of (R) configuration and (S) configuration. Either one of theisomers or a mixture thereof can be employed in the present invention.

The compounds represented by the above general formula (I) and thepharmaceutically acceptable salts thereof of the present invention havean excellent inhibitory activity in human SGLT2 and are extremely usefulas agents for the prevention or treatment of a disease associated withhyperglycemia such as diabetes, diabetic complication or obesity. In thefollowing assay for inhibitory effect on human SGLT2 activity, compoundsof the present invention exerted a potent inhibitory activity in humanSGLT2.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry sirups, tablets, capsules, injections,solutions, ointments, suppositories, poultices and the like areillustrated, which are orally or parenterally administered.

These pharmaceutical compositions can be prepared by admixing with or bydiluting and dissolving an appropriate pharmaceutical additive such asexcipients, disintegrators, binders, lubricants, diluents, buffers,isotonicities, antiseptics, moistening agents, emulsifiers, dispersingagents, stabilizing agents, dissolving aids and the like, andformulating the mixture in accordance with conventional.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a compoundrepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof of the present invention as the activeingredient is appropriately decided depending on the age, sex, bodyweight and degree of symptoms and treatment of each patient, which isapproximately within the range of from 0.1 to 1,000 mg per day per adulthuman in the case of oral administration and approximately within therange of from 0.01 to 300 mg per day per adult human in the case ofparenteral administration, and the daily dose can be divided into one toseveral doses per day and administered suitably.

EXAMPLE

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples. However,the present invention is not limited thereto.

Reference Example 1 Methyl 4-[(2-benzyloxyphenyl)hydroxymethyl]benzoate

A Grignard reagent was prepared from 1-benzyloxy-2-bromobenzene (5.3 g),magnesium (0.49 g) and tetrahydrofuran (160 mL). The obtained Grignardreagent was added to a solution of methyl 4-formylbenzoate (3.3 g) intetrahydrofuran (60 mL), and the mixture was stirred at room temperaturefor 1 hour. To the reaction mixture were added water and dilutehydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate, and the solvent was removed under reducedpressure. The residue was purified by column chromatography onaminopropyl silica gel (eluent: hexane/ethyl acetate=4/1) to give methyl4-[(2-benzyloxyphenyl)hydroxymethyl]benzoate (2.6 g).

¹H-NMR (CDCl₃) δ ppm:

3.02 (1H, d, J=6.3 Hz), 3.91 (3H, s), 5.00 (1H, d, J=11.6 Hz), 5.04 (1H,d, J=11.6 Hz), 6.07 (1H, d, J=6.3 Hz), 6.90-7.05 (2H, m), 7.15-7.35 (7H,m), 7.35-7.45 (2H, m), 7.90-8.00 (2H, m)

Example 1 Methyl 4-(2-hydroxybenzyl)benzoate

To a solution of methyl 4-[(2-benzyloxyphenyl)-hydroxymethyl]benzoate(2.6 g) in ethanol (15 mL) was added 10% palladium-carbon powder (0.50g), and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 18 hours. An insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure to give methyl 4-(2-hydroxybenzyl)benzoate (1.7 g).

¹H-NMR (CDCl₃) δ ppm:

3.89 (3H, s), 4.04 (2H, s), 4.80 (1H, s), 6.75-6.80 (1H, m), 6.85-6.95(1H, m), 7.05-7.20 (2H, m), 7.25-7.35 (2H, m), 7.90-8.00 (2H, m)

Reference Example 2 Methyl 4-(2-benzyloxybenzyl)benzoate

To a suspension of methyl 4-(2-hydroxybenzyl)benzoate (1.5 g) andpotassium carbonate (0.94 g) in N,N-dimethylformamide (200 mL) was addedbenzylbromide (0.81 mL), and the mixture was stirred at 50° C. for 5hours. An insoluble material was removed by filtration, water and dilutehydrochloric acid was added to the filtrate, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brineand dried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to givemethyl 4-(2-benzyloxybenzyl)benzoate (2.1 g).

¹H-NMR (CDCl₃) δ ppm:

3.89 (3H, s), 4.06 (2H, s), 5.03 (2H, s), 6.85-6.95 (2H, m), 7.10-7.40(9H, m), 7.85-7.95 (2H, m)

Reference Example 3 4-(2-Benzyloxybenzyl)benzyl alcohol

To a suspension of lithium aluminum hydride (0.47 g) in tetrahydrofuran(5 mL) was added dropwise a solution of methyl4-(2-benzyloxybenzyl)benzoate (2.1 g) in tetrahydrofuran (5 mL) at 0°C., and the mixture was stirred at the same temperature for 1 hour.Ethyl acetate (10 mL) was added to the reaction mixture, and theresulting mixture was stirred for 30 minutes. To the reaction mixturewere added water and dilute hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brineand dried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure to give 4-(2-benzyloxybenzyl)benzyl alcohol (1.9g).

¹H-NMR (CDCl₃) δ ppm:

4.02 (2H, s), 4.65 (2H, s), 5.06 (2H, s), 6.85-6.95 (2H, m), 7.05-7.40(11H, m)

Reference Example 4 4-(2-Benzyloxybenzyl)benzaldehyde

To a solution of 4-(2-benzyloxybenzyl)benzyl alcohol (1.0 g) indichloromethane (50 mL) was added manganese (II) oxide (10 g), and themixture was stirred at room temperature for 3 hours. An insolublematerial was removed by filtration, and the solvent of the filtrate wasremoved under reduced pressure to give 4-(2-benzyloxybenzyl)benzaldehyde(0.97 g).

¹H-NMR (CDCl₃) δ ppm:

4.08 (2H, s), 5.03 (2H, s), 6.90-7.00 (2H, m), 7.10-7.40 (9H, m),7.70-7.80 (2H, m), 9.96 (1H, s)

Reference Example 5 Ethyl (E)-3-[4-(2-hydroxybenzyl)phenyl]acrylate

To a solution of triethyl phosphonoacetate (0.89 mL) in tetrahydrofuran(30 mL) was added potassium tert-butoxide (0.50 g), and the mixture wasstirred at room temperature for 15 minutes. A solution of4-(2-benzyloxybenzyl)benzaldehyde (1.0 g) in tetrahydrofuran (10 mL) wasadded to the reaction mixture, and the mixture was stirred at roomtemperature for 6 hours. To the reaction mixture was added dilutehydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: hexane/ethyl acetate=10/1) to give ethyl(E)-3-[4-(2-benzyloxybenzyl)phenyl]acrylate (0.86 g). To the obtainedethyl (E)-3-[4-(2-benzyloxybenzyl)phenyl]acrylate (0.86 g) were addedtrifluoroacetic acid (9.5 mL), water (0.5 mL) and dimethyl sulfide (1.0mL), and the mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, and the residue was purifiedby column chromatography on silica gel (eluent: hexane/ethylacetate=3/1) to give ethyl (E)-3-[4-(2-hydroxybenzyl)phenyl]acrylate(0.51 g).

¹H-NMR (CDCl₃) δ ppm:

1.33 (3H, t, J=7.2 Hz), 4.01 (2H, s), 4.26 (2H, q, J=7.2 Hz), 4.96 (1H,s), 6.38 (1H, d, J=16.1 Hz), 6.75-6.80 (1H, m), 6.85-6.95 (1H, m),7.05-7.20 (2H, m), 7.20-7.30 (2H, m), 7.40-7.50 (2H, m), 7.65 (1H, d,J=16.1 Hz)

Reference Example 6 (E)-2-[4-(2-Ethoxycarbonylvinyl)benzyl]phenylβ-D-glucopyranoside

To a suspension of ethyl (E)-3-[4-(2-hydroxybenzyl)-phenyl]acrylate(0.34 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (1.4 g) indichloromethane (3 mL) and toluene (9 ml) was added borontrifluoride-diethyl ether complex (0.45 mL), and the mixture was stirredat room temperature overnight. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: hexane/ethylacetate=4/1) to give(E)-2-[4-(2-ethoxy-carbonylvinyl)benzyl]phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.47 g). To a solution ofthe obtained (E)-2-[(4-(2-ethoxycarbonylvinyl)benzyl]phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.46 g) in methanol (5 mL)was added sodium methoxide (0.0 log), and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: ethyl acetate) to give(E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl β-D-glucopyranoside (0.31g).

¹H-NMR (CD₃OD) δ ppm:

1.31 (3H, t, J=7.2 Hz), 3.30-3.55 (4H, m), 3.68 (1H, dd, J=5.3, 12.0Hz), 3.88 (1H, dd, J=1.9, 12.0 Hz), 4.00 (1H, d, J=14.9 Hz), 4.15 (1H,dd, J=14.9 Hz), 4.22 (2H, q, J=7.2 Hz), 4.92 (1H, d, J=7.1 Hz), 6.45(1H, d, J=16.1 Hz), 6.90-7.00 (1H, m), 7.05-7.20 (3H, m), 7.25-7.35 (2H,m), 7.45-7.55 (2H, m), 7.64 (1H, d, J=16.1 Hz)

Reference Example 7 2-(4-Methoxycarbonylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

To a suspension of methyl 4-(2-hydroxybenzyl)benzoate (0.053 g) and1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.26 g) in dichloromethane(1 mL) and toluene (3 mL) was added boron trifluoride-diethyl ethercomplex (0.083 mL), and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and the residue was purified by column chromatography on silica gel(eluent: hexane/ethyl acetate=4/1) to give2-(4-methoxycarbonyl-benzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.067 g).

¹H-NMR (CDCl₃) δ ppm:

1.87 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.07 (3H, s), 3.80-4.05 (6H,m), 4.16 (1H, dd, J=2.7, 12.4 Hz), 4.28 (1H, dd, J=5.8, 12.4 Hz),5.10-5.20 (2H, m), 5.25-5.35 (2H, m), 6.95-7.10 (3H, m), 7.15-7.25 (3H,m), 7.90-7.95 (2H, m)

Reference Example 8 4-Allyloxy-2′-(methoxymethyloxy)diphenylmethanol

A Grignard reagent was prepared from 1-allyloxy-4-bromobenzene (1.7 g),magnesium (0.19 g), a catalytic amount of iodine and tetrahydrofuran (3mL). To the obtained Grignard reagent was added a solution of2-(methoxymethyloxy)-benzaldehyde (0.88 g) in tetrahydrofuran (19 mL),and the mixture was stirred at room temperature for 30 minutes. Asaturated aqueous ammonium chloride solution was added to the reactionmixture, and the resulting mixture was extracted with ethyl acetate. Theorganic layer was washed with water and brine and dried over anhydroussodium sulfate, and the solvent was removed under reduced pressure. Theresidue was purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=5/1) to give4-allyloxy-2′-(methoxymethyloxy)diphenylmethanol (1.2 g).

¹H-NMR (CDCl₃) δ ppm:

2.78 (1H, d, J=5.4 Hz), 3.31 (3H, s), 4.45-4.55 (2H, m), 5.12 (1H, d,J=7.0 Hz), 5.14 (1H, d, J=7.0 Hz), 5.20-5.30 (1H, m), 5.35-5.45 (1H, m),5.95-6.10 (2H, m), 6.80-6.90 (2H, m), 6.95-7.05 (1H, m), 7.07 (1H, dd,J=0.9, 8.2 Hz), 7.20-7.35 (3H, m), 7.35 (1H, dd, J=1.8, 7.7 Hz)

Reference Example 9 4-Allyloxy-2′-(methoxymethyloxy)benzophenone

To a solution of 4-allyloxy-2′-(methoxymethyloxy)-diphenylmethanol (1.2g) in dichloromethane (20 mL) was added a Dess-Martin reagent(1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) (2.1 g)at 0° C., and the mixture was stirred for 1 hour. The reaction mixturewas warmed to ambient temperature and stirred overnight. Diethyl etherand 1 mol/L aqueous sodium hydroxide solution were added to the reactionmixture, and the organic layer was separated. The organic layer waswashed with 1 mol/L aqueous sodium hydroxide solution, water and brine,and dried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure to give4-allyloxy-2′-(methoxymethyloxy)benzophenone (1.1 g).

¹H-NMR (CDCl₃) δ ppm:

3.33 (3H, s), 4.55-4.65 (2H, m), 5.08 (2H, s), 5.25-5.35 (1H, m),5.35-5.50 (1H, m), 6.00-6.15 (1H, m), 6.85-7.00 (2H, m), 7.05-7.15 (1H,m), 7.15-7.25 (1H, m), 7.33 (1H, dd, J=1.5, 7.7 Hz), 7.35-7.50 (1H, m),7.75-7.85 (2H, m)

Reference Example 10 4-Allyloxy-2′-hydroxybenzophenone

To a solution of 4-allyloxy-2′-(methoxymethyloxy)-benzophenone (1.1 g)in ethanol (15 mL) was added concentrated hydrochloric acid (0.96 mL),and the mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, and a saturated aqueoussodium hydrogen carbonate solution was added to the residue. The mixturewas extracted with ethyl acetate. The organic layer was washed withbrine and dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=15/1) to give4-allyloxy-2′-hydroxybenzophenone (0.87 g).

¹H-NMR (CDCl₃) δ ppm:

4.60-4.70 (2H, m), 5.30-5.40 (1H, m), 5.40-5.50 (1H, m), 6.00-6.15 (1H,m), 6.85-6.95 (1H, m), 6.95-7.05 (2H, m), 7.07 (1H, dd, J=1.0, 8.4 Hz),7.45-7.55 (1H, m), 7.63 (1H, dd, J=1.6, 8.0 Hz), 7.65-7.75 (2H, m),11.96 (1H, s)

Example 2 2-(4-Allyloxybenzyl)phenol

To a solution of 4-allyloxy-2′-hydoxybenzophenone (0.87 g) intetrahydrofuran (14 mL) were added triethylamine (0.53 mL) and methylchloroformate (0.29 mL) at 0° C., and the mixture was stirred at roomtemperature for 1.5 hours. An insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure. To a solution of the residue in tetrahydrofuran (18 mL) andwater (9 mL) was added sodium borohydride (0.52 g) at 0° C., and themixture was stirred at room temperature for 2.5 hours. To the reactionmixture was added 0.5 mol/L aqueous hydrochloric acid solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, and dried over anhydrous sodium sulfate, and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent: hexane/ethyl acetate=8/1)to give 2-(4-allyloxybenzyl)phenol (0.72 g).

¹H-NMR (CDCl₃) δ ppm:

3.93 (2H, s), 4.45-4.55 (2H, m), 4.73 (1H, brs), 5.20-5.30 (1H, m),5.35-5.45 (1H, m), 5.95-6.10 (1H, m), 6.78 (1H, dd, J=1.3, 7.9 Hz),6.80-6.95 (3H, m), 7.05-7.20 (4H, m)

Reference Example 11 2-(4-Allyloxybenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

To a solution of 2-(4-allyloxybenzyl)phenol (0.20 g) and2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose(0.45g) in dichloromethane(8.5 mL) was added boron trifluoride-diethyl ethercomplex (0.12 g), and the mixture was stirred at room temperature for 2hours. A saturated aqueous sodium hydrogen carbonate solution was addedto the reaction mixture, and the resulting mixture was extracted withethyl acetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate, and the solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: hexane/ethyl acetate=1/1) to give2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside(0.44 g).

¹H-NMR (CDCl₃) δ ppm:

1.90 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.07 (3H, s), 3.80-3.95 (3H,m), 4.18 (1H, dd, J=2.5, 12.3 Hz), 4.28 (1H, dd, J=5.5, 12.3 Hz),4.45-4.55 (2H, m), 5.11 (1H, d, J=7.5 Hz), 5.10-5.45 (5H, m), 5.95-6.10(1H, m), 6.75-6.85 (2H, m), 6.95-7.10 (5H, m), 7.10-7.20 (1H, m)

Reference Example 124-(2-Benzyloxyethyl)-2′-(methoxymethyloxy)diphenylmethanol

The title compound was prepared in a similar manner to that described inReference Example 8 using 4-(2-benzyloxy-ethyl)-1-bromobenzene insteadof 4-allyloxy-1-bromobenzene.

¹H-NMR (CDCl₃) δ ppm:

2.80 (1H, d, J=5.7 Hz), 2.90 (2H, t, J=7.1 Hz), 3.30 (3H, s), 3.66 (2H,t, J=7.1 Hz), 4.51 (2H, s), 5.10-5.20 (2H, m), 6.06 (1H, d, J=5.7 Hz),6.95-7.05 (1H, m), 7.05-7.10 (1H, m), 7.10-7.20 (2H, m), 7.20-7.40 (9H,m)

Reference Example 134-(2-Benzyloxyethyl)-2′-(methoxymethyloxy)benzophenone

The title compound was prepared in a similar manner to that described inReference Example 9 using4-(2-benzyl-oxyethyl)-2′-(methoxymethyloxy)diphenylmethanol instead of4-allyloxy-2′-(methoxymethyloxy)diphenylmethanol.

¹H-NMR (CDCl₃) δ ppm:

2.98 (2H, t, J=6.8 Hz), 3.29 (3H, s), 3.72 (2H, t, J=6.8 Hz), 4.51 (2H,s), 5.05 (2H, s), 7.05-7.15 (1H, m), 7.15-7.25 (1H, m), 7.25-7.40 (8H,m), 7.40-7.50 (1H, m), 7.70-7.80 (2H, m)

Reference Example 14 4-(2-Benzyloxyethyl)-2′-hydroxybenzophenone

The title compound was prepared in a similar manner to that described inReference Example 10 using4-(2-benzyl-oxyethyl)-2′-(methoxymethyloxy)benzophenone instead of4-allyloxy-2′-(methoxymethyloxy)benzophenone.

¹H-NMR (CDCl₃) δ ppm:

3.02 (2H, t, J=6.8 Hz), 3.75 (2H, t, J=6.8 Hz), 4.55 (2H, s), 6.85-6.90(1H, m), 7.05-7.10 (1H, m), 7.25-7.40 (7H, m), 7.45-7.55 (1H, m),7.55-7.65 (3H, m), 12.02 (1H, s)

Example 3 2-[4-(2-Benzyloxyethyl)benzyl]phenol

The title compound was prepared in a similar manner to that described inExample 2 using 4-(2-benzyloxyethyl)-2′-hydroxybenzophenone instead of4-allyloxy-2′-hydroxy-benzophenone.

¹H-NMR (CDCl₃) δ ppm:

2.90 (2H, t, J=7.2 Hz), 3.66 (2H, t, J=7.2 Hz), 3.97 (2H, s), 4.52 (2H,s), 4.62 (1H, s), 6.75-6.85 (1H, m), 6.85-6.95 (1H, m), 7.05-7.20 (6H,m), 7.20-7.40 (5H, m)

Reference Example 15 4-(2-Benzyloxybenzyl)benzyl chloride

To a solution of 4-(2-benzyloxybenzyl)benzyl alcohol (0.67 g) indichloromethane (30 mL) was added thionyl chloride (0.48 mL), and themixture was heated under reflux for 1 hour. The reaction mixture wasconcentrated under reduced pressure, water was added to the residue, andthe resulting mixture was extracted with diethyl ether. The organiclayer was washed with brine and dried over anhydrous sodium sulfate, andthe solvent was removed under reduced pressure to give4-(2-benzyloxy-benzyl)benzyl chloride (0.68 g).

¹H-NMR (CDCl₃) δ ppm:

4.01 (2H, s), 4.56 (2H, s), 5.04 (2H, s), 6.85-7.40 (13H, m)

Reference Example 16 [4-(2-Benzyloxybenzyl)phenyl]acetonitrile

To a solution of 4-(2-benzyloxybenzyl)benzyl chloride (0.66 g) inN,N-dimethylformamide (20 mL) was added potassium cyanide (0.40 g), andthe mixture was stirred at 60° C. for 18 hours. The reaction mixture wascooled to ambient temperature, and water was added thereto. Theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous sodium hydrogen carbonate solutionand brine, and dried over anhydrous magnesium sulfate, and the solventwas removed under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=5/1-3/1) togive [4-(2-benzyloxybenzyl)phenyl]acetonitrile (0.54 g).

¹H-NMR (CDCl₃) δ ppm:

3.70 (2H, s), 4.01 (2H, s), 5.04 (2H, s), 6.85-7.40 (13H, m)

Example 4 [4-(2-Hydroxybenzyl)phenyl]acetonitrile

Trifluoroacetic acid (17 mL), water (1 mL) and dimethyl sulfide (2 mL)were added to [4-(2-benzyloxybenzyl)phenyl]-acetonitrile (0.41 g), andthe mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent: hexane/ethylacetate=3/1) to give [4-(2-hydroxybenzyl)phenyl]acetonitrile (0.26 g).

¹H-NMR (CDCl₃) δ ppm:

3.71 (2H, s), 3.99 (2H, s), 4.76 (1H, s), 6.77 (1H, dd, J=1.1, 7.9 Hz),6.89 (1H, dt, 1.1, 7.5 Hz), 7.05-7.20 (2H, m), 7.20-7.30 (4H, m)

Reference Example 17 4-(2-Benzyloxybenzyl)benzoic acid

To a solution of methyl 4-(2-benzyloxybenzyl)benzoate (1.0 g) inmethanol (20 mL) was added 2 mol/L aqueous sodium hydroxide solution(7.5 mL), and the mixture was stirred at 60° C. for-5 hours. Thereaction mixture was concentrated under reduced pressure. After theresidue was acidified by adding dilute hydrochloric acid, the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over anhydrous magnesium sulfate, and the solventwas removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzoicacid (0.72 g).

¹H-NMR (DMSO-d₆) δ ppm:

4.01 (2H, s), 5.09 (2H, s), 6.85-6.95 (1H, m), 7.00-7.10 (1H, m),7.15-7.40 (9H, m), 7.75-7.85 (2H, m), 12.77 (1H, brs)

Reference Example 18 4-(2-Benzyloxybenzyl)benzamide

To a suspension of 4-(2-benzyloxybenzyl)benzoic acid (0.70 g) indichloromethane (10 mL) was added thionyl chloride (0.48 mL), and themixture was stirred at 50° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure, and 28% aqueous ammonium solution(50 mL) was added to the residue. The mixture was stirred at roomtemperature for 30 minutes. An insoluble material was collected byfiltration, washed with water then hexane, and dried under reducedpressure to give 4-(2-benzyloxybenzyl)benzamide (0.62 g).

¹H-NMR (DMSO-d₆) δ ppm:

3.98 (2H, s), 5.10 (2H, s), 6.85-6.95 (1H, m), 7.00-7.10 (1H, m),7.15-7.40 (10H, m), 7.70-7.80 (2H, m), 7.88 (1H, brs)

Example 5 4-(2-Hydroxybenzyl)benzamide

To a solution of 4-(2-benzyloxybenzyl)benzamide (0.50 g) in ethanol (10mL) was added 10% palladium-carbon powder (0.10 μg), and the mixture wasstirred under a hydrogen atmosphere at room temperature for 1 hour. Aninsoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give4-(2-hydroxybenzyl)benzamide (0.31 g).

¹H-NMR (DMSO-d₆) δ ppm:

3.90 (2H, s), 6.65-6.75 (1H, m), 6.75-6.85 (1H, m), 6.95-7.10 (2H, m),7.20-7.30 (3H, m), 7.70-7.80 (2H, m), 7.86 (1H, brs), 9.40 (1H, s)

Reference Example 19 2-Benzyloxy-4′-(N,N-dimethylamino)diphenylmethanol

The title compound was prepared in a similar manner to that described inReference Example 8 using 2-benzyloxy-1-bromobenzene and4-(N,N-dimethylamino)benzaldehyde instead of 4-allyloxy-1-bromobenzeneand 2-(methoxymethyloxy)-benzaldehyde.

¹H-NMR (CDCl₃) δ ppm:

2.77 (1H, d, J=5.3 Hz), 2.93 (6H, s), 5.04 (2H, s), 6.03 (1H, d, J=5.3Hz), 6.65-6.75 (2H, m), 6.85-7.05 (2H, m), 7.15-7.45 (9H, m)

Example 6 2-[4-(N,N-Dimethylamino)benzyl]phenol

To a solution of 2-benzyloxy-4′-(N,N-dimethylamino)-diphenylmethanol(0.85 g) in ethanol (25 mL) was added 10% palladium-carbon powder (0.34g), and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 22 hours. An insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: hexane/ethyl acetate=4/1) to give2-[4-(N,N-dimethylamino)-benzyl]phenol (0.35 g).

¹H-NMR (CDCl₃) δ ppm:

2.91 (6H, s), 3.91 (2H, s), 4.73 (1H, s), 6.65-6.75 (2H, m), 6.75-6.85(1H, m), 6.85-6.95 (1H, m), 7.05-7.20 (4H, m)

Reference Example 20 2-[4-(N,N-Dimethylamino)benzyl]phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 11 using 2-[4-(N,N-dimethyl-amino)benzyl]phenolinstead of 2-(4-allyloxybenzyl)phenol.

¹H-NMR (CDCl₃) δ ppm:

1.92 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.08 (3H, s), 2.89 (6H, s),3.80-3.90 (3H, m), 4.18 (1H, dd, J=2.3, 12.2 Hz), 4.28 (1H, dd, J=5.7,12.2 Hz), 5.09 (1H, d, J=7.7 Hz), 5.15-5.25 (1H, m), 5.25-5.40 (2H, m),6.60-6.70 (2H, m), 6.90-7.10 (5H, m), 7.10-7.20 (1H, m)

Reference Example 21 4-Benzyloxy-2′-(methoxymethyloxy)diphenylmethanol

The title compound was prepared in a similar manner to that described inReference Example 8 using 1-bromo-2-(methoxy-methyloxy)benzene and4-benzyloxybenzaldehyde instead of 1-allyloxy-4-bromobenzene and2-(methoxymethyloxy)-benzaldehyde.

¹H-NMR (CDCl₃) δ ppm:

2.78 (1H, d, J=5.4 Hz), 3.29 (3H, s), 5.04 (2H, s), 5.10-5.20 (2H, m),6.03 (1H, d, J=5.4 Hz), 6.85-6.95 (2H, m), 6.95-7.10 (2H, m), 7.20-7.45(9H, m)

Reference Example 22 4-Benzyoxy-2′-(methoxymethyloxy)benzophenone

The title compound was prepared in a similar manner to that described inReference Example 9 using4-benzyloxy-2′-(methoxymethyloxy)diphenylmethanol instead of4-allyloxy-2′-(methoxymethyloxy)diphenylmethanol.

¹H-NMR (CDCl₃) δ ppm:

3.31 (3H, s), 5.07 (2H, s), 5.13 (2H, s), 6.95-7.05 (2H, m), 7.05-7.15(1H, m), 7.15-7.25 (1H, m), 7.30-7.50 (7H, m), 7.75-7.85 (2H, m)

Reference Example 23 4-Benxyloxy-2′-hydroxybenzophenone

The title compound was prepared in a similar manner to that described inReference Example 10 using 4-benzyloxy-2′-(methoxymethyloxy)benzophenoneinstead of 4-allyloxy-2′-(methoxymethyloxy)benzophenone.

¹H-NMR (CDCl₃) δ ppm:

5.16 (2H, s), 6.85-6.95 (1H, m), 7.00-7.10 (3H, m), 7.30-7.55 (6H, m),7.63 (1H, dd, J=1.9, 8.2 Hz), 7.65-7.75 (2H, m), 11.95 (1H, s)

Example 7 2-[(4-Benzyloxy)benzyl]phenol

The title compound was prepared in a similar manner to that described inExample 2 using 4-benzyloxy-2′-hydroxy-benzophenone instead of4-allyloxy-2′-hydroxybenzophenone.

¹H-NMR (CDCl₃) δ ppm:

3.94 (2H, s), 4.70 (1H, s), 5.03 (2H, s), 6.75-6.80 (1H, m), 6.85-6.95(3H, m), 7.05-7.20 (4H, m), 7.25-7.45 (5H, m)

Reference Example 24 2-[(4-Benzyloxy)benzyl]phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 11 using 2-[4-(benzyloxy)-benzyl]phenol instead of2-(4-allyloxybenzyl)phenol.

¹H-NMR (CDCl₃) δ ppm:

1.88 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.07 (3H, s), 3.80-3.90 (3H,m), 4.17 (1H, dd, J=2.4, 12.3 Hz), 4.28 (1H, dd, J=5.7, 12.3 Hz), 5.03(2H, s), 5.10 (1H, d, J=7.2 Hz), 5.15-5.25 (1H, m), 5.25-5.40 (2H, m),6.85-6.90 (2H, m), 6.95-7.10 (5H, m), 7.10-7.20 (1H, m), 7.25-7.45 (5H,m)

Reference Example 25 1-Bromo-4-[2-(methoxymethyloxy)ethyl]benzene

To a solution of 2-(4-bromophenyl)ethanol (1.0 g) anddiisopropylethylamine (1.3 mL) in dichloromethane (5 mL) was addedchloromethyl methyl ether (0.75 mL), and the mixture was stirred at roomtemperature for 2 hours. To the reaction mixture was added water, andthe organic layer was separated and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure. The residue was purifiedby column chromatography on silica gel (eluent: hexane/ethylacetate=15/1-10/1) to give 1-bromo-4-[2-(methoxymethyloxy)ethyl]-benzene(1.2 g).

¹H-NMR (CDCl₃) δ ppm:

2.85 (2H, t, J=6.8 Hz), 3.28 (3H, s), 3.74 (2H, t, J=6.8 Hz), 4.60 (2H,s), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m)

Reference Example 262-Hydroxy-4-methoxy-4′-[2-(methoxymethyloxy)ethyl]diphenyl-methanol

To a solution of 1-bromo-4-[2-(methoxymethyloxy)-ethyl]benzene (0.61 g)in tetrahydrofuran (12 mL) was added tert-butyl lithium (1.5 mol/Lpentane solution, 1.8 mL) under an argon atmosphere at −78° C., and themixture was stirred for 30 minutes. A solution of2-hydroxy-4-methoxybenzaldehyde (0.15 g) in tetrahydrofuran (6 mL) wasadded to the reaction mixture, and the mixture was warmed to 0° C. andstirred for 25 minutes. A saturated aqueous ammonium chloride solutionwas added to the reaction mixture, and the mixture was extracted withdiethyl ether. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=2/1) to give2-hydroxy-4-methoxy-4′-[2-(methoxymethyloxy)ethyl]diphenyl-methanol(0.31 g).

¹H-NMR (CDCl₃) δ ppm:

2.77 (1H, d, J=2.9 Hz), 2.90 (2H, t, J=6.9 Hz), 3.29 (3H, s), 3.70-3.80(5H, m), 4.61 (2H, s), 5.96 (1H, d, J=2.9 Hz), 6.35 (1H, dd, J=2.1, 8.5Hz), 6.48 (1H, d, J=2.1 Hz), 6.70 (1H, d, J=8.5 Hz), 7.20-7.35 (4H, m),8.04 (1H, s)

Example 8 5-Methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenol

To a solution of2-hydroxy-4-methoxy-4′-[2-(methoxy-methyloxy)ethyl]diphenylmethanol(0.31g) in ethanol(10 mL) was added 10% palladium-carbon powder (0.061 g),and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 1 hour. An insoluble material was removed by filtration,and the solvent of the filtrate was removed under reduced pressure. Theresidue was purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=5/2) to give5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenol (0.19 g).

¹H-NMR (CDCl₃) δ ppm:

2.86 (2H, t, J=7.0 Hz), 3.29 (3H, s), 3.74 (2H, t, J=7.0 Hz), 3.76 (3H,s), 3.90 (2H, s), 4.61 (2H, s), 4.77 (1H, s), 6.38 (1H, d, J=2.5 Hz),6.45 (1H, dd, J=2.5, 8.5 Hz), 7.01 (1H, d, J=8.5 Hz), 7.10-7.20 (4H, m)

Reference Example 275-Methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

To a solution of5-methoxy-2-{4-[2-(methoxymethyl-oxy)ethyl]benzyl}phenol (0.19 g) and2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.40g) in dichloromethane (15 mL) was added boron trifluoride-diethyl ethercomplex (0.088 mL) at 0° C., and the mixture was stirred 20 minutes. Asaturated aqueous sodium hydrogen carbonate solution was added to thereaction mixture, and the organic layer was separated. The organic layerwas dried over anhydrous sodium sulfate, and the solvent was removedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.33 g).

¹H-NMR (CDCl₃) δ ppm:

1.85 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.10 (3H, s), 2.85 (2H, t,J=7.1 Hz), 3.30 (3H, s), 3.72 (2H, t, J=7.1 Hz), 3.77 (3H, s), 3.75-3.85(2H, m), 3.80-3.95 (1H, m), 4.19 (1H, dd, J=2.4, 12.2 Hz), 4.25 (1H, dd,J=5.9, 12.2 Hz), 4.60 (2H, s), 5.07 (1H, d, J=7.7 Hz), 5.10-5.20 (1H,m), 5.25-5.35 (2H, m), 6.53 (1H, dd, J=2.5, 8.7 Hz), 6.65 (1H, d, J=2.5Hz), 6.94 (1H, d, J=8.7 Hz), 7.00-7.20 (4H, m)

Reference Example 28 Methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate

To a solution methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (1.28 g) inN,N-dimethylformamide (14 mL) were added potassium carbonate (0.98 g)and benzyl bromide (0.62 mL), and the mixture was stirred at roomtemperature for 19 hours. The reaction mixture was poured into water,and the mixture was extracted twice with diethyl ether. The combinedorganic layer was washed with water and dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=5/1) to give methyl3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g).

¹H-NMR (CDCl₃) δ ppm:

1.22 (3H, t, J=7.7 Hz), 2.61 (2H, q, J=7.7 Hz), 3.90 (3H, s), 4.02 (2H,s), 5.11 (2H, s), 7.00-7.20 (5H, m), 7.25-7.40 (5H, m), 7.55-7.65 (2H,m)

Reference Example 29 3-Benzyloxy-4-(4-ethylbenzyl)benzoic acid

Methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g) was dissolved in amixed solvent of tetrahydrofuran (5 mL) and ethanol (5 mL). To thesolution was added 2 mol/L aqueous sodium hydroxide solution (10 mL),and the mixture was stirred at 80° C. for 1 hour. The reaction mixturewas cooled to ambient temperature, acidified with 2 mol/L hydrochloricacid, and the mixture was stirred under ice-cooling for 30 minutes. Theresulting precipitated crystals were collected by filtration, washedwith water and dried to give 3-benzyloxy-4-(4-ethylbenzyl)benzoic acid(1.4 g).

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (3H, t, J=7.6 Hz), 2.55 (2H, q, J=7.6 Hz), 3.96 (2H, s), 5.18 (2H,s), 7.05-7.15 (4H, m), 7.20-7.40 (6H, m), 7.50 (1H, dd, J=1.5, 7.9 Hz),7.55 (1H, d, J=1.5 Hz), 12.84 (1H, s)

Example 9 5-Amino-2-(4-ethylbenzyl)phenol

To a solution of 3-benzyloxy-4-(4-ethylbenzyl)benzoic acid (1.4 g) andtriethylamine (1.3 mL) in 1,4-dioxane (10 mL) was added a solution ofdiphenylphosphoryl azide (1.3 g) in 1,4-dioxane (10 mL), and the mixturewas stirred at 100° C. for 1 hour. Benzyl alcohol (1.6 mL) was added tothe reaction mixture, and the mixture was stirred at the sametemperature for 7 hours. The solvent of the reaction mixture was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to givebenzyl N-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]carbamate (1.4 g). To asolution of obtained benzylN-[3-benzyloxy-4-(4-ethyl-benzyl)phenyl]carbamate (1.4 g) in methanol(15 mL) was added 10% palladium-carbon powder (0.28 g), and the mixturewas stirred under a hydrogen atmosphere for 11 hours. An insolublematerial was removed by filtration, and the solvent of the filtrate wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give5-amino-2-(4-ethylbenzyl)phenol(0.54 g).

¹H-NMR (CDCl₃) δ ppm:

1.21 (3H, t, J=7.7 Hz), 2.61 (2H, q, J=7.7 Hz), 3.56 (2H, brs), 3.85(2H, s), 4.57 (1H, s), 6.18 (1H, d, J=2.4 Hz), 6.25 (1H, dd, J=2.4, 8.1Hz), 6.89 (1H, d, J=8.1 Hz), 7.05-7.15 (4H, m)

Example 10 Benzyl N-[4-(4-ethylbenzyl)-3-hydroxyphenyl]carbamate

To a solution of 5-amino-2-(4-ethylbenzyl)phenol (0.25 g) intetrahydrofuran (10 mL) was added N-benzyloxycarbonyloxy-succinimide(0.41 g), and the mixture was stirred at room temperature for 22 hours.The reaction mixture was purified by column chromatography on silica gel(eluent: hexane/ethyl acetate=5/1) to give benzylN-[4-(4-ethylbenzyl)-3-hydroxyphenyl]carbamate (0.40 g).

¹H-NMR (CDCl₃) δ ppm:

1.21 (3H, t, J=7.7 Hz), 2.60 (2H, q, J=7.7 Hz), 3.90 (2H, s), 5.00 (1H,brs), 5.19 (2H, s), 6.59 (1H, brs), 6.70 (1H, dd, J=2.3, 8.2 Hz), 7.01(1H, d, J=8.2 Hz), 7.05-7.20 (5H, m), 7.30-7.45 (5H, m)

Reference Example 30 5-Benzyloxycarbonylamino-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 27 using benzylN-[4-(4-ethylbenzyl)-3-hydroxyphenyl]carbamate instead of5-methoxy-2-[4-(2-methoxymethyloxy)ethylbenzyl]phenol.

¹H-NMR (CDCl₃) δ ppm:

1.19 (3H, t, J=7.5 Hz), 1.85 (3H, s), 2.02 (3H, s), 2.03 (3H, s), 2.05(3H, s), 2.59 (2H, q, J=7.5 Hz), 3.70-3.95 (3H, m), 4.10-4.40 (2H, m),5.00-5.40 (6H, m), 6.63 (1H, brs), 6.74 (1H, dd, J=1.9, 8.2 Hz), 6.95(1H, d, J=8.2 Hz), 6.95-7.10 (4H, m), 7.20-7.60 (6H, m)

Reference Example 31 5-Amino-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

To a solution of 5-benzyloxycarbonylamino-2-(4-ethyl-benzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.35 g) in tetrahydrofuran(4 mL) was added 10% palladium-carbon powder (0.07 g), and the mixturewas stirred under a hydrogen atmosphere at room temperature for 8 hours.An insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent: hexane/ethylacetate=2/3-dichloromethane/ethyl acetate=1/1) to give5-amino-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.19 g).

¹H-NMR (CDCl₃) δ ppm:

1.19 (3H, t, J=7.6 Hz), 1.84 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.09(3H, s), 2.59 (2H, q, J=7.6 Hz), 3.59 (2H, brs), 3.70-3.90 (3H, m), 4.18(1H, dd, J=2.5, 12.2 Hz), 4.28 (1H, dd, J=5.3, 12.2 Hz), 5.04 (1H, d,J=7.5 Hz), 5.10-5.35 (3H, m), 6.34 (1H, dd, J=2.1, 8.0 Hz), 6.42 (1H, d,J=2.1 Hz), 6.82 (1H, d, J=8.0 Hz), 6.95-7.15 (4H, m)

Reference Example 32 2-(Methoxymethyloxy)-4,6-dimethylbenzaldehyde

To a solution of 2-hydroxy-4,6-dimethylbenzaldehyde (0.75 g) andN,N-diisopropylethylamine (1.4 mL) in dichloro-methane (20 mL) was addedchloromethyl methyl ether (0.57 mL), and the mixture was stirred at roomtemperature for 24 hours. Water was added to the reaction mixture, andthe mixture was extracted with diethyl ether. The organic layer waswashed with brine and dried over anhydrous sodium sulfate, and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent: hexane/ethyl acetate=20/1)to give 2-(methoxymethyloxy)-4,6-dimethyl-benzaldehyde (0.57 g).

¹H-NMR (CDCl₃) δ ppm:

2.34 (3H, s), 2.55 (3H, s), 3.51 (3H, s), 5.26 (2H, s), 6.65-6.70 (1H,m), 6.85-6.90 (1H, m), 10.61 (1H, s)

Reference Example 334′-(3-Benzyloxypropyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethanol

A Grignard reagent was prepared from1-(3-benzyloxy-propyl)-4-bromobenzene (1.3 g), magnesium (0.1 g), acatalytic amount of iodine and tetrahydrofuran (4.4 mL). To the obtainedGrignard reagent solution was added a solution of2-(methoxy-methyloxy)-4,6-dimethylbenzaldehyde (0.57 g) intetrahydro-furan (10 mL), and the mixture was stirred for 20 minutes. Asaturated aqueous ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and brine, and dried over anhydrous sodiumsulfate, and the solvent was removed under reduce pressure. The residuewas purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=4/1) to give4′-(3-benzyloxypropyl)-2-(methoxy-methyloxy)-4,6-dimethyldiphenylmethanol(1.1 g).

¹H-NMR (CDCl₃) δ ppm:

1.80-1.95 (2H, m), 2.31 (3H, s), 2.32 (3H, s), 2.60-2.75 (2H, m), 3.12(3H, s), 3.46 (2H, t, J=6.2 Hz), 3.91 (1H, d, J=10.7 Hz), 4.49 (2H, s),4.93 (1H, d, J=6.5 Hz), 5.03 (1H, d, J=6.5 Hz), 6.03 (1H, d, J=10, 7Hz), 6.70-6.75 (1H, m), 6.75-6.80 (1H, m), 7.05-7.10 (2H, m), 7.15-7.20(2H, m), 7.20-7.40 (5H, m)

Reference Example 344′-(3-Hydroxypropyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethane

To a solution of4′-(3-benzyloxypropyl)-2-(methoxy-methyloxy)-4,6-dimethyldiphenylmethanol(1.1 g) in ethanol (27 mL) was added 10% palladium-carbon powder (0.46g), and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 17 hours. An insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure to give4′-(3-hydroxypropyl)-2-(methoxy-methyloxy)-4,6-dimethyldiphenylmethane(0.85 g).

¹H-NMR (CDCl₃) δ ppm:

1.80-1.90 (2H, m), 2.20 (3H, s), 2.30 (3H, s), 2.60-2.70 (2H, m), 3.36(3H, s), 3.60-3.70 (2H, m), 4.00 (2H, s), 5.13 (2H, s), 6.65-6.70 (1H,m), 6.75-6.85 (1H, m), 7.00-7.10 (4H, m)

Reference Example 354′-(3-Benzoyloxypropyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethane

To a solution of4′-(3-hydroxypropyl)-2-(methoxy-methyloxy)-4,6-dimethyl-diphenylmethane(0.85 g), triethylamine (0.49 mL) and 4-(dimethylamino)pyridine (0.033g) in dichloromethane (14 mL) was added benzyl chloride (0.38 mL), andthe mixture was stirred at room temperature for 18 hours. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate, and the solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: hexane/ethyl acetate=20/1) to give4′-(3-benzoyloxypropyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethane(1.1 g).

¹H-NMR (CDCl₃) δ ppm:

2.00-2.10 (2H, m), 2.20 (3H, s), 2.30 (3H, s), 2.65-2.75 (2H, m), 3.36(3H, s), 4.00 (2H, s), 4.25-4.35 (2H, m), 5.13 (2H, s), 6.65-6.70 (1H,m), 6.75-6.85 (1H, m), 7.00-7.10 (4H, m), 7.40-7.50 (2H, m), 7.50-7.60(1H, m), 8.00-8.10 (2H, m)

Example 11 2-[4-(3-Benzoyloxypropyl)benzyl]-3,5-dimethylphenol

To a solution of4′-(3-benzoyloxypropyl)-2-(methoxy-methyloxy)-4,6-dimethyldiphenylmethane(1.1 g) in methanol (13 mL) was added p-toluenesulfonic acid monohydrate(0.096 g), and the mixture was stirred at 60° C. for 4 hours. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=6/1) to give2-[4-(3-benzoyloxypropyl)-benzyl]-3,5-dimethylphenol (0.89 g).

¹H-NMR (CDCl₃) δ ppm:

2.00-2.10 (2H, m), 2.23 (3H, s), 2.26 (3H, s), 2.65-2.80 (2H, m), 3.98(2H, s), 4.25-4.35 (2H, m), 4.53 (1H, s), 6.45-6.55 (1H, m), 6.60-6.70(1H, m), 7.00-7.15 (4H, m), 7.40-7.50 (2H, m), 7.50-7.60 (1H, m),8.00-8.10 (2H, m)

Example 364′-(2-Benzyloxyethyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethanol

The title compound was prepared in a similar manner to that described inReference Example 33 using 1-(2-benzyl-oxyethyl)-4-bromobenzene insteadof 1-(3-benzyloxypropyl)-4-bromobenzene.

¹H-NMR (CDCl₃) δ ppm:

2.30 (3H, s), 2.32 (3H, s), 2.89 (2H, t, J=7.3 Hz), 3.13 (3H, s), 3.64(2H, t, J=7.3 Hz), 3.89 (1H, d, J=10.7 Hz), 4.50 (2H, s), 4.93 (1H, d,J=6.6 Hz), 5.02 (1H, d, J=6.6 Hz), 6.03 (1H, d, J=10.7 Hz), 6.70-6.75(1H, m), 6.75-6.80 (1H, m), 7.10-7.35 (9H, m)

Reference Example 374′-(2-hydroxyethyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethane

The title compound was prepared in a similar manner to that described inReference Example 34 using4′-(2-benzyl-oxyethyl)-2-(methoxymethyloxy)-4,6-dimetyldiphenylmethanolinstead of4′-(3-benzyloxypropyl)-2-(methoxymethyloxy)-4,6-dimethyldiphenylmethanol.

¹H-NMR (CDCl₃) δ ppm:

1.31 (1H, t, J=5.9 Hz), 2.20 (3H, s), 2.30 (3H, s), 2.80 (2H, t, J=6.5Hz), 3.37 (3H, s), 3.75-3.85 (2H, m), 4.01 (2H, s), 5.13 (2H, s),6.65-6.70 (1H, m), 6.75-6.85 (1H, m), 7.05-7.10 (4H, m)

Reference Example 384′-(2-Benzoyloxyethyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethane

The title compound was prepared in a similar manner to that described inReference Example 35 using4′-(2-hydroxy-ethyl)-2-(methoxymethyloxy)-4,6-dimetyldiphenylmethaneinstead of4′-(3-hydroxypropyl)-2-(methoxymethyloxy)-4,6-dimethyldiphenylmethane.

¹H-NMR (CDCl₃) δ ppm:

2.19 (3H, s), 2.30 (3H, s), 3.01 (2H, t, J=7.0 Hz), 3.33 (3H, s), 4.01(2H, s), 4.47 (2H, t, J=7.0 Hz), 5.11 (2H, s), 6.65-6.70 (1H, m),6.75-6.85 (1H, m), 7.00-7.10 (2H, m), 7.10-7.15 (2H, m), 7.35-7.45 (2H,m), 7.50-7.60 (1H, m), 7.95-8.05 (2H, m)

Example 12 2-[4-(2-Benzoyloxyethyl)benzyl]-3,5-dimethylphenol

The title compound was prepared in a similar manner to that described inExample 11 using4′-(2-benzoyloxyethyl)-2-(methoxymethyloxy)-4,6-dimethyldiphenylmethaneinstead of4′-(3-benzoyloxypropyl)-2-(methoxymethyloxy)-4,6-dimethyl-diphenylmethane.

¹H-NMR (CDCl₃) δ ppm:

2.22 (3H, s), 2.25 (3H, s), 3.02 (2H, t, J=7.0 Hz), 3.99 (2H, s), 4.49(2H, t, J=7.0 Hz), 4.60 (1H, brs), 6.45-6.55 (1H, m), 6.60-6.65 (1H, m),7.05-7.20 (4H, m), 7.35-7.45 (2H, m), 7.50-7.60 (1H, m), 7.95-8.05 (2H,m)

Reference Example 39 2-(4-Ethylbenzyl)-5-(methylamino)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

To a solution of 5-benzyloxycarbonylamino-2-(4-ethyl-benzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.42 g) and iodomethane(0.067 mL) in tetrahydrofuran (7 mL) was added sodium hydride (60%,0.034 g) at 0° C. The reaction mixture was warmed to ambient temperatureand stirred for another 5 hours. Iodomethane (0.13 mL) and sodiumhydride (60%, 0.020 g) were added to the reaction mixture, and themixture was stirred for additional 1 hour. The reaction mixture waspoured into water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by column chromatography on aminopropyl silica gel (eluent:hexane/ethyl acetate=2/1) to give5-(N-benzyloxycarbonyl-N-methyl)amino-2-(4-ethylbenzyl)-phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.30 g). To a solution ofthe obtained5-(N-benzyloxycarbonyl-N-methyl)-amino-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.30 g) in tetrahydrofuran(5 mL) was added 10% palladium-carbon powder (0.060 g), and the mixturewas stirred under a hydrogen atmosphere at room temperature for 6 hours.An insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent: hexane/ethyl acetate=1/1)to give 2-(4-ethylbenzyl)-5-(methylamino)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.15 g).

¹H-NMR (CDCl₃) δ ppm:

1.19 (3H, t, J=7.7 Hz), 1.84 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.06(3H, s), 2.58 (2H, q, J=7.7 Hz), 2.81 (3H, s), 3.65 (1H, brs), 3.70-3.95(3H, m), 4.18 (1H, dd, J=2.5, 12.3 Hz), 4.26 (1H, dd, J=5.0, 12.3 Hz),5.07 (1H, d, J=7.7 Hz), 5.10-5.20 (1H, m), 5.20-5.35 (2H, m), 6.28 (1H,dd, J=2.3, 8.2 Hz), 6.36 (1H, d, J=2.3 Hz), 6.85 (1H, d, J=8.2 Hz),7.00-7.10 (4H, m)

Example 13 4-(4-Ethylbenzyl)-3-hydroxybenzamide

To a mixture of methyl 4-(4-ethylbenzyl)-3-hydroxy-benzoate (0.20 g) and28% aqueous ammonia solution (6 mL) in ethanol (3 mL) was added ammoniumchloride (0.079 g), and the mixture was stirred in sealed tube at 100°C. for 14 hours. The reaction mixture was concentrated under reducedpressure, water was added to the residue, and the resulting mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure. Amixed solvent of dichloromethane and methanol (10:1) was added to theresidue, and an insoluble material was collected by filtration and driedto give 4-(4-ethylbenzyl)-3-hydroxybenzamide (0.065 g).

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (3H, t, J=7.6 Hz), 2.54 (2H, q, J=7.6 Hz), 3.85 (2H, s), 7.00-7.15(6H, m), 7.21 (1H, dd, J=1.7, 7.8 Hz), 7.29 (1H, d, J=1.7 Hz), 7.72 (1H,brs), 9.56 (1H, s)

Reference Example 40 5-Carbamoyl-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 27 using 4-(4-ethyl-benzyl)-3-hydroxybenzamide insteadof 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenol.

¹H-NMR (CD₃OD) δ ppm:

1.19 (3H, t, J=7.6 Hz), 1.85 (3H, s), 1.99 (3H, s), 2.04 (6H, s), 2.56(2H, q, J=7.6 Hz), 3.80-4.00 (2H, m), 4.00-4.35 (3H, m), 5.05-5.20 (1H,m), 5.20-5.30 (1H, m), 5.30-5.45 (2H, m), 6.95-7.20 (5H, m), 7.40-7.55(1H, m), 7.55-7.65 (1H, m)

Reference Example 41 2-Hydroxy-4-(methoxymethyloxy)benzaldehyde

To a suspension of 2,4-dihydroxybenzaldehyde (0.83 g) and cesiumcarbonate (1.7 g) in acetonitrile (30 mL) was added chloromethyl methylether (0.55 mL), and the mixture was stirred at room temperature for 30minutes. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and the solvent was removed under reduced pressure. Theresidue was purified by column chromatography on silica gal (eluent:hexane/ethyl acetate=4/1) to give2-hydroxy-4-(methoxymethyloxy)benzaldehyde (0.84 g).

¹H-NMR (CDCl₃) δ ppm:

3.48 (3H, s), 5.22 (2H, s), 6.60 (1H, d, J=2.2 Hz), 6.65 (1H, dd, J=2.2,8.6 Hz), 7.45 (1H, d, J=8.6 Hz), 9.74 (1H, s), 11.37 (1H, s)

Reference Example 424′-Ethyl-2-hydroxy-4-(methoxymethyloxy)diphenylmethanol

To a solution of 1-bromo-4-ethylbenzene (0.46 g) in tetrahydrofuran (12mL) was added tert-butyl lithium (1.45 mol/L pentane solution, 1.9 mL)under an argon atmosphere at −78° C., and the mixture was stirred for 30minutes. To the reaction mixture was added a solution of2-hydroxy-4-methoxymethyl-oxybenzaldehyde(0.18 g) in tetrahydrofuran(6mL). The mixture was warmed to 0° C. and stirred for additional 15minutes. A saturated aqueous ammonium chloride solution was added to thereaction mixture, and the mixture was extracted with diethyl ether. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas removed under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give4′-ethyl-2-hydroxy-4-(methoxymethyloxy)diphenylmethanol (0.30 g).

¹H-NMR (CDCl₃) δ ppm:

1.23 (3H, t, J=7.5 Hz), 2.64 (2H, q, J=7.5 Hz), 2.80 (1H, d, J=3.1 Hz),3.45 (3H, s), 5.12 (2H, s), 5.95 (1H, d, J=3.1 Hz), 6.47 (1H, dd, J=2.5,8.5 Hz), 6.61 (1H, d, J=2.5 Hz), 6.72 (1H, d, 8,5 Hz), 7.15-7.25 (2H,m), 7.25-7.35 (2H, m), 8.07 (1H, s)

Example 14 2-(4-Ethylbenzyl)-5-(methoxymethyloxy)phenol

To a solution of4′-ethyl-2-hydroxy-4-(methoxymethyl-oxy)diphenylmethanol (0.14 g) inethanol (5 mL) was added 10% palladium-carbon powder (0.058 g), and themixture was stirred under a hydrogen atmosphere at room temperature for1 hour. An insoluble material was removed by filtration, and the solventof the filtrate was removed under reduced pressure. The residue waspurified by column chromatography on silica gel (eluent: hexane/ethylacetate=4/1) to give 2-(4-ethylbenzyl)-5-(methoxymethyloxy)phenol (0.12g).

¹H-NMR (CDCl₃) δ ppm:

1.21 (3H, t, J=7.6 Hz), 2.61 (2H, q, J=7.6 Hz), 3.47 (3H, s), 3.90 (2H,s), 4.73 (1H, s), 5.13 (2H, s), 6.53 (1H, d, J=2.2 Hz), 6.58 (1H, dd,J=2.2, 8.1 Hz), 7.02 (1H, d, J=8.1 Hz), 7.10-7.15 (4H, m)

Reference Example 43 2-(4-Ethylbenzyl)-5-(methoxymethyloxy)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 27 using 2-(4-ethyl-benzyl)-5-(methoxymethyloxy)phenolinstead of 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenol.

¹H-NMR (CDCl₃) δ ppm:

1.19 (3H, t, J=7.6 Hz), 1.85 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.10(3H, s), 2.59 (2H, q, J=7.6 Hz), 3.46 (3H, s), 3.79 (1H, d, J=15.5 Hz),3.84 (1H, d, J=15.5 Hz), 3.85-3.95 (1H, m), 4.19 (1H, dd, J=2.3, 12.2Hz), 4.27 (1H, dd, J=5.5, 12.2 Hz), 5.05-5.25 (4H, m), 5.25-5.40 (2H,m), 6.69 (1H, dd, J=2.4, 8.4 Hz), 6.68 (1H, d, J=2.4 Hz), 6.96 (1H, d,J=8.4 Hz), 7.00-7.15 (4H, m)

Example 15 2-(4-Methoxybenzyl)-3,5-dimethylphenol

To 3,5-dimethylphenol (12 g) were added lithium hydroxide monohydrate(4.2 g) and 4-methoxybenzyl chloride (14 mL) at 85° C., and the mixturewas stirred 1.5 hours. The reaction mixture was cooled to ambienttemperature and purified by column chromatography on silica gel (eluent:dichloromethane) to give 2-(4-methoxybenzyl)-3,5-dimethylphenol (5.1 g).

¹H-NMR (CDCl₃) δ ppm:

2.24 (3H, s), 2.26 (3H, s), 3.77 (3H, s), 3.94 (2H, s), 4.53 (1H, s),6.45-6.55 (1H, m), 6.55-6.65 (1H, m), 6.75-6.85 (2H, m), 7.00-7.10 (2H,m)

Reference Example 44 2-(4-Methoxybenzyl)-3,5-dimethylphenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

To a solution of 2-(4-methoxybenzyl)-3,5-dimethylphenol (4.0 g) and2,3,4,6-tetra-O-acetyl-1-O-trichloroaceto-imidoyl-α-D-glucopyranose (8.9g) in dichloromethane (100 mL) was added boron trifluoride diethyl-ethercomplex (2.5 mL) at 0° C., and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was purified by columnchromatography on aminopropyl silica gel (eluent: dichloromethane). Thesolvent was removed under reduced pressure, ethanol was added to theresidue, and the resulting crystals were collected by filtration. Theobtained crystals were dried under reduced pressure to give2-(4-methoxybenzyl)-3,5-dimethylphenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7.8 g).

¹H-NMR (CDCl₃) δ ppm:

1.65 (3H, s), 2.00 (3H, s), 2.04 (3H, s), 2.09 (3H, s), 2.12 (3H, s),2.30 (3H, s), 3.74 (3H, s), 3.78 (1H, d, J=15.5 Hz), 3.80-3.95 (1H, m),4.00 (1H, d, J=15.5 Hz), 4.18 (1H, dd, J=2.5, 12.2 Hz), 4.24 (1H, dd,J=5.8, 12.2 Hz), 5.00-5.20 (2H, m), 5.20-5.35 (2H, m), 6.70-6.80 (4H,m), 6.85-7.00 (2H, m)

Example 16 3-Hydroxy-4-(4-methoxybenzyl)benzamide

The title compound was prepared in a similar manner to that described inExample 13 using methyl 3-hydroxy-4-(4-methoxybenzyl)benzoate instead ofmethyl 4-(4-ethylbenzyl)-3-hydroxybenzoate. Purification was carried outby column chromatography on silica gel (eluent:dichloromethane/methanol=8/1).

¹H-NMR (CD₃OD) δ ppm:

3.74 (3H, s), 3.89 (2H, s), 6.75-6.85 (2H, m), 7.03 (1H, d, J=7.8 Hz),7.05-7.15 (2H, m), 7.21 (1H, dd, J=1.6, 7.8 Hz), 7.27 (1H, d, J=1.6 Hz)

Reference Example 45 3-Hydroxy-4-(4-methoxybenzyl)benzonitrile

To a solution of 3-hydroxy-4-(4-methoxybenzyl)benzamide (0.047 g) andtriethylamine (0.30 mL) in dichloromethane (1.8 mL) was addedtrifluoromethanesulfonic anhydride (0.34 mL), and the mixture wasstirred at room temperature overnight. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure. The residue was purified by preparativethin layer chromatography on silica gel (eluent:dichloromethane/methanol=9/1) to give3-hydroxy-4-(4-methoxybenzyl)benzonitrile (0.014 g).

¹H-NMR (CDCl₃) δ ppm:

3.80 (3H, s), 4.06 (2H, s), 6.80-6.90 (2H, m), 7.05-7.15 (2H, m), 7.25(1H, d, J=8.0 Hz), 7.66 (1H, dd, J=1.6, 8.0 Hz), 7.76 (1H, d, J=1.6 Hz)

Reference Example 46 5-Cyano-2-(4-methoxybenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 27 using 3-hydroxy-4-(4-methoxybenzyl)benzonitrileinstead of 5-methoxy-2-(4-[2-(methoxymethyloxy)ethyl]benzyl)phenol.

¹H-NMR (CDCl₃) δ ppm:

1.93 (3H, s), 2.04 (3H, s), 2.07 (3H, s), 2.14 (3H, s), 3.78 (3H, s),3.87 (2H, s), 3.90-4.00 (1H, m), 4.15-4.30 (2H, m), 5.05-5.20 (2H, m),5.25-5.45 (2H, m), 6.75-6.90 (2H, m), 6.95-7.10 (2H, m), 7.10-7.20 (1H,m), 7.20-7.35 (2H, m)

Reference Example 47 2-Hydroxy-4,4′-dimethoxydiphenylmethanol

The title compound was prepared in a similar manner to that described inReference Example 26 using 4-bromoanisole instead of1-bromo-4-[2-(methoxymethyloxy)ethyl]benzene.

¹H-NMR (CDCl₃) δ ppm:

2.66 (1H, d, J=3.0 Hz), 3.77 (3H, s), 3.81 (3H, s), 5.95 (1H, d, J=3.0Hz), 6.36 (1H, dd, J=2.6, 8.5 Hz), 6.49 (1H, d, J=2.6 Hz), 6.69 (1H, d,J=8.5 Hz), 6.85-6.95 (2H, m), 7.25-7.35 (2H, m), 8.10 (1H, s)

Example 17 5-Methoxy-2-(4-methoxybenzyl)phenol

The title compound was prepared in a similar manner to that described inExample 8 using 2-hydroxy-4,4′-dimethoxy-diphenylmethanol instead of2-hydroxy-4-methoxy-4′-[2-(methoxymethyloxy)ethyl]diphenylmethanol.

¹H-NMR (CDCl₃) δ ppm:

3.77 (3H, s), 3.78 (3H, s), 3.87 (2H, s), 4.67 (1H, s), 6.39 (1H, d,J=2.5 Hz), 6.46 (1H, dd, J=2.5, 8.3 Hz), 6.75-6.90 (2H, m), 7.01 (1H, d,J=8.3 Hz), 7.05-7.20 (2H, m)

Reference Example 48 5-Methoxy-2-(4-methoxybenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 27 using 5-methoxy-2-(4-methoxybenzyl)phenol insteadof 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenol.

¹H-NMR (CDCl₃) δ ppm:

1.88 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.09 (3H, s), 3.70-3.95 (9H,m), 4.19 (1H, dd, J=2.5, 12.2 Hz), 4.25 (1H, dd, J=5.9, 12.2 Hz), 5.07(1H, d, J=7.4 Hz), 5.10-5.40 (3H, m), 6.54 (1H, dd, J=2.4, 8.4 Hz), 6.65(1H, d, J=2.4 Hz), 6.75-6.85 (2H, m), 6.94 (1H, d, J=8.4 Hz), 7.00-7.10(2H, m)

Reference Example 49 3-Benzyloxy-4-(4-ethylbenzyl)benzyl alcohol

To a solution of methyl 4-(4-ehtylbenzyl)-3-hydroxy-benzoate (1.3 g) inN,N-dimethylformamide (15 mL) were added potassium carbonate (0.79 g)and benzyl bromide (0.62 mL), and the mixture was stirred at roomtemperature for 13 hours. Water was added to the reaction mixture, andthe mixture was extracted with diethyl ether. The organic layer waswashed with water and dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue was dissolved indiethyl ether (10 mL). The resulting solution was added to a suspensionof lithium aluminium hydride (0.57 g) in diethyl ether (50 mL) at 0° C.,and the mixture was heated under reflux for 1.5 hours. The reactionmixture was cooled to 0° C., water (0.60 mL), 15% aqueous sodiumhydroxide solution (0.60 mL) and water (1.8 mL) were successively addedto the reaction mixture, and the mixture was stirred for 5 minutes. Aninsoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent: hexane/ethyl acetate=2/1)to give 3-benzyloxy-4-(4-ethylbenzyl)benzyl alcohol (1.3 g).

¹H-NMR (CDCl₃) δ ppm:

1.22 (3H, t, J=7.7 Hz), 1.57 (1H, t, J=6.2 Hz), 2.61 (2H, q, J=7.7 Hz),3.98 (2H, s), 4.65 (2H, d, J=6.2 Hz), 5.07 (2H, s), 6.87 (1H, dd, J=1.1,7.5 Hz), 6.97 (1H, d, J=1.1 Hz), 7.05-7.15 (5H, m), 7.25-7.40 (5H, m)

Reference Example 50 [3-Benzyloxy-4-(4-ethylbenzyl)phenyl]acetonitrile

To a solution of 3-benzyloxy-4-(4-ethylbenzyl)benzyl alcohol (0.87 g) indichloromethane (20 mL) were added triethylamine (0.44 mL) andmethanesulfonyl chloride (0.22 mL) at 0° C., and the mixture was stirredfor 2 hours. To the reaction mixture was added 0.5 mol/L aqueoushydrochloric acid solution, and the mixture was extracted with diethylether. The organic layer was washed with water and a saturated aqueoussodium hydrogen carbonate solution, and dried over anhydrous magnesiumsulfate, and the solvent was removed under reducer pressure. The residuewas dissolved in dimethyl sulfoxide (10 mL). To the solution were addedpotassium cyanide (0.68 g) and a catalytic amount of sodium iodide, andthe resulting mixture was stirred at 80° C. for 12 hours. Water wasadded to the reaction mixture, and the mixture was extracted withdiethyl ether. The organic layer was washed with water and dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: hexane/ethyl acetate=5/1-3/1) to give[3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetonitrile (0.41 g).

¹H-NMR (CDCl₃) δ ppm:

1.22 (3H, t, J=7.5 Hz), 2.61 (2H, q, J=7.5 Hz), 3.70 (2H, s), 3.97 (2H,s), 5.07 (2H, s), 6.80-6.90 (2H, m), 7.05-7.15 (5H, m), 7.25-7.45 (5H,m)

Reference Example 51 2-[3-Benzyloxy-4-(4-ethylbenzyl)phenyl]acetamide

To a mixture of [3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetonitrile (0.41g) in ethanol (5 mL) and water (10 mL) was added potassium hydroxide(0.68 g), and the mixture was heated under reflux for 4 hours. Thereaction mixture was acidified by adding 2 mol/L aqueous hydrochloricacid solution, and the mixture was extracted with diethyl ether. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure to give[3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g). To a solutionof the obtained [3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetic acid (0.41g) in tetrahydrofuran (10 mL) were added pyridine (0.19 mL),di-tert-butyl dicarbonate (0.50 g) and ammonium hydrogen carbonate (0.18g), and the mixture was stirred at room temperature for 18 hours. To thereaction mixture was added 1 mol/L aqueous hydrochloric acid solution,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give2-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetamide (0.38 g).

¹H-NMR (DMSO-d₆) δ ppm:

1.14 (3H, t, J=7.5 Hz), 2.53 (2H, q, J=7.5 Hz), 3.25-3.40 (2H, m), 3.85(2H, s), 5.06 (2H, s), 6.78 (1H, dd, J=1.0, 7.9 Hz), 6.84 (1H, brs),6.98 (1H, d, J=1.0 Hz), 7.00-7.10 (5H, m), 7.25-7.45 (6H, m)

Reference Example 52 2-[(4-(4-Ethylbenzyl)-3-hydroxyphenyl]acetamide

To a solution of 2-[3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetamide (0.38g) in methanol (5 mL) was added 10% palladium-carbon powder (0.075 g),and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 4 hours. An insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: dichloromethane/methanol=30/1-20/1) to give2-[4-(4-ethylbenzyl)-3-hydroxyphenyl]acetamide (0.16 g).

¹H-NMR (DMSO-d₆) δ ppm:

1.13 (3H, t, J=7.6 Hz), 2.53 (2H, q, J=7.6 Hz), 3.22 (2H, s), 3.77 (2H,s), 6.59 (1H, dd, J=1.5, 7.7 Hz), 6.72 (1H, d, J=1.5 Hz), 6.81 (1H,brs), 6.90 (1H, d, J=7.7 Hz), 7.00-7.15 (4H, m), 7.37 (1H, brs), 9.27(1H, s)

Reference Example 53 5-Carbamoylmethyl-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 27 using2-[4-(4-ethyl-benzyl)-3-hydroxyphenyl]acetamide instead of5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenol.

¹H-NMR (CDCl₃) δ ppm:

1.20 (3H, t, J=7.6 Hz), 1.88 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.07(3H, s), 2.60 (2H, q, J=7.6 Hz), 3.53 (2H, s), 3.80-3.95 (3H, m),4.15-4.30 (2H, m), 5.13 (1H, d, J=7.1 Hz), 5.15-5.25 (1H, m), 5.25-5.40(3H, m), 5.48 (1H, brs), 6.91 (1H, dd, J=1.4, 7.9 Hz), 6.97 (1H, d,J=1.4 Hz), 7.00-7.15 (5H, m)

Reference Example 542-Hydroxy-4′-methoxy-4-(methoxymethyl)diphenylmethanol

The title compound was prepared in a similar manner to that described inReference Example 26 using 4-bromoanisole and2-hydroxy-4-methoxymethylbenzaldehyde instead of1-bromo-4-[2-(methoxymethyloxy)ethyl]benzene and2-hydroxy-4-methoxy-benzaldehyde.

¹H-NMR (CDCl₃) δ ppm:

2.71 (1H, d, J=3.1 Hz), 3.37 (3H, s), 3.80 (3H, s), 4.39 (2H, s), 5.99(1H, d, J=3.1 Hz), 6.70-6.85 (2H, m), 6.85-6.95 (3H, m), 7.25-7.35 (2H,m), 7.98 (1H, s)

Example 18 2-(4-Methoxybenzyl)-5-methoxymethylphenol

To a solution of 2-hydroxy-4′-methoxy-4-(methoxy-methyl)diphenylmethanol(0.17 g) in ethanol (11 mL) was added 10% palladium-carbon powder (0.051g), and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 30 minutes. An insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: hexane/ethyl acetate=3/1-2/1) to give2-(4-methoxy-benzyl)-5-methoxymethylphenol (0.082 g).

¹H-NMR (CDCl₃) δ ppm:

3.38 (3H, s), 3.78 (3H, s), 3.92 (2H, s), 4.39 (2H, s), 4.77 (1H, s),6.75-6.90 (4H, m), 7.00-7.20 (3H, m)

Reference Example 55 2-(4-Methoxybenzyl)-5-methoxymethylphenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 27 using 2-(4-methoxy-benzyl)-5-methoxymethylphenolinstead of 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenol.

¹H-NMR (CDCl₃) δ ppm:

1.90 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.08 (3H, s), 3.37 (3H, s),3.77 (3H, s), 3.84 (2H, s), 3.85-3.95 (1H, m), 4.10-4.30 (2H, m),4.30-4.50 (2H, m), 5.10-5.25 (2H, m), 5.25-5.40 (2H, m), 6.75-6.85 (2H,m), 6.90-7.10 (5H, m)

Reference Example 565-Methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenylβ-D-glucopyranoside

To a solution of5-methoxy-2-{4-[2-(methoxymethyl-oxy)ethyl]benzyl}phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.13 g) in methanol (8 mL)was added 2 mol/L aqueous sodium hydroxide solution (0.50 mL), and themixture was stirred at room temperature for 25 minutes. The solvent wasremoved under reduced pressure, and the residue was purified bypreparative thin layer chromatography on silica gel (eluent:dichloromethane/methanol=7/1) to give5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenylβ-D-glucopyranoside (0.053 g).

¹H-NMR (CD₃OD) δ ppm:

2.81 (2H, t, J=6.9 Hz), 3.24 (3H, s), 3.30-3.55 (4H, m), 3.60-3.75 (3H,m), 3.75 (3H, s), 3.88 (1H, d, J=15.0 Hz), 3.90 (1H, dd, J=2.0, 12.0Hz), 4.00 (1H, d, J=15.0 Hz), 4.57 (2H, s), 4.85-4.95 (1H, m), 6.50 (1H,dd, J=2.5, 8.3 Hz), 6.79 (1H, d, J=2.5 Hz), 6.93 (1H, d, J=8.3 Hz),7.05-7.20 (4H, m)

Reference Example 57 5-[2-(Benzyloxy)ethyloxy]-2-(4-ethylbenzyl)phenylβ-D-glucopyranoside

To a suspension of 2-(4-ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside(0.039 g) and cesium carbonate (0.098 g) in N,N-dimethylformamide (1 mL)was added (2-bromoethyl)benzyl ether (0.025 mL), and the mixture wasstirred at 50° C. for 3.5 hours. The reaction mixture was cooled toambient temperature, water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and the solvent was removed under reducedpressure. The residue was purified by preparative thin layerchromatography on silica gel (eluent: dichloromethane/methanol=6/1) togive 5-[2-(benzyloxy)ethyloxy]-2-(4-ethylbenzyl)phenylβ-D-glucopyranoside (0.022 g).

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6 Hz), 3.30-3.55 (4H, m), 3.67(1H, dd, J=5.4, 12.1 Hz), 3.75-3.85 (2H, m), 3.86 (1H, d, J=15.0 Hz),3.88 (1H, dd, J=2.0, 12.1 Hz), 3.98 (1H, d, J=15.0 Hz), 4.05-4.15 (2H,m), 4.58 (2H, s), 4.80-4.90 (1H, m), 6.52 (1H, dd, J=2.4, 8.5 Hz), 6.81(1H, d, J=2.4 Hz), 6.93 (1H, d, J=8.5 Hz), 7.00-7.20 (4H, m), 7.20-7.40(5H, m)

Example 19 (E)-2-[4-(3-hydroxy-1-prop-1-ene-1-yl)benzyl]phenylβ-D-glucopyranoside

To a suspension of lithium aluminium hydride (0.036 g) intetrahydrofuran (5 mL) was added(E)-2-[4-(2-ethoxycarbonyl-vinyl)benzyl]phenyl β-D-glucopyranoside(0.035 g) at 0° C., and the mixture was stirred for 1 hour. Ethylacetate (10 mL) was added to the reaction mixture, and the mixture wasstirred for 30 minutes. To the reaction mixture were added water anddilute hydrochloric acid, and the resulting mixture was extracted withethylacetate. The organic layer was washed with brine and dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure to give (E)-2-[4-(3-hydroxy-1-prop-1-ene-1-yl)benzyl]phenylβ-D-glucopyranoside (0.028 g).

¹H-NMR (CD₃OD) δ ppm:

3.35-3.55 (4H, m), 3.69 (1H, dd, J=5.0, 12.0 Hz), 3.88 (1H, dd, J=1.8,12.0 Hz), 3.96 (1H, d, J=14.9 Hz), 4.09 (1H, d, J=14.9 Hz), 4.15-4.25(2H, m), 4.91 (1H, d, J=7.5 Hz), 6.30 (1H, dt, J=5.9, 16.0 Hz),6.50-6.60 (1H, m), 6.85-7.25 (6H, m), 7.25-7.35 (2H, m)

Example 20 2-(4-Methoxycarbonylbenzyl)phenyl β-D-glucopyranoside

To a solution of 2-(4-methoxycarbonylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.066 g) in methanol (5 mL)was added sodium methoxide (0.006 g), and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: ethyl acetate) to give2-(4-methoxycarbonyl-benzyl)phenyl β-D-glucopyranoside (0.040 g).

¹H-NMR (CD₃OD) δ ppm:

3.30-3.55 (4H, m), 3.68 (1H, dd, 5.4, 11.9 Hz), 3.85-3.95 (4H, m), 4.05(1H, d, J=14.8 Hz), 4.19 (1H, d, J=14.8 Hz), 4.91 (1H, d, J=7.2 Hz),6.90-7.00 (1H, m), 7.05-7.15 (1H, m), 7.15-7.20 (2H, m), 7.30-7.40 (2H,m), 7.85-7.95 (2H, m)

Example 21 2-(4-Allyloxybenzyl)phenyl β-D-glucopyranoside

To a solution of 2-(4-allyloxybenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g) in methanol (2.5 mL)and tetrahydrofuran (1.5 mL) was added sodium methoxide (28% methanolsolution, 0.30 mL), and the mixture was stirred at room temperature for4 hours. The solvent of the reaction mixture was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: dichloro-methane/methanol=10/1) to give2-(4-allyloxybenzyl)phenyl β-D-glucopyranoside (0.23 g).

¹H-NMR (CD₃OD) δ ppm:

3.30-3.55 (4H, m), 3.69 (1H, dd, J=4.9, 11.9 Hz), 3.88 (1H, dd, J=2.0,11.9 Hz), 3.92 (1H, d, J=14.8 Hz), 4.03 (1H, d, J=14.8 Hz), 4.45-4.55(2H, m), 4.91 (1H, d, J=7.4 Hz), 5.15-5.25 (1H, m), 5.30-5.40 (1H, m),5.95-6.10 (1H, m), 6.75-6.85 (2H, m), 6.85-6.95 (1H, m), 7.00-7.10 (1H,m), 7.10-7.20 (4H, m)

Example 22 2-[4-(2-Benzyloxyethyl)benzyl]phenyl β-D-glucopyranoside

To a solution of 2-[4-(2-benzyloxyethyl)benzyl]phenol (3.2 g) and1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (12 g) in toluene (34 mL) anddichloromethane (17 mL) was added boron trifluoride diethyl-ethercomplex (3.8 mL), and the mixture was stirred at room temperature for 14hours. A saturated aqueous sodium hydrogen carbonate solution was addedto the reaction mixture, and the resulting mixture was extracted withethyl acetate. The organic layer was washed with a saturated aqueoussodium hydrogen carbonate solution and brine, and dried over anhydroussodium sulfate, and the solvent was removed under reduced pressure. Theresidue was dissolved in methanol (50 mL), sodium methoxide (28%methanol solution, 0.39 mL) was added to the solution, and the mixturewas stirred at room temperature for 2.5 hours. The solvent of thereaction mixture was removed under reduced pressure, water was added tothe residue, and the resulting mixture was extracted with ethylacetate.The organic layer was washed with brine and dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give2-[4-(2-benzyloxyethyl)benzyl]phenyl β-D-glucopyranoside (3.4 g).

¹H-NMR (CD₃OD) δ ppm:

2.84 (2H, t, J=7.0 Hz), 3.35-3.55 (4H, m), 3.60-3.75 (3H, m), 3.88 (1H,dd, J=2.0, 12.0 Hz), 3.96 (1H, d, J=14.9 Hz), 4.07 (1H, d, J=14.9 Hz),4.48 (2H, s), 4.91 (1H, d, J=7.4 Hz), 6.85-6.95 (1H, m), 7.00-7.20 (7H,m), 7.20-7.35 (5H, m)

Example 23 2-(4-Carboxybenzyl)phenyl β-D-glucopyranoside

To a solution of 2-[4-(methoxycarbonyl)benzyl]phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.050 g) in methanol (1 mL)was added 2 mol/L aqueous sodium hydroxide solution (0.26 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas purified by column chromatography on benzenesulfonylpropyl silicagel (eluent: methanol) to give 2-(4-carboxybenzyl)phenylβ-D-glucopyranoside (0.038 g).

¹H-NMR (CD₃OD) δ ppm:

3.30-3.55 (4H, m), 3.69 (1H, dd, J=5.1, 12.1 Hz), 3.88 (1H, dd, J=2.0,12.1 Hz), 4.04 (1H, d, J=14.8 Hz), 4.19 (1H, d, J=14.8 Hz), 4.85-5.00(1H, m), 6.85-7.00 (1H, m), 7.05-7.15 (1H, m), 7.15-7.20 (2H, m),7.30-7.40 (2H, m), 7.85-7.95 (2H, m)

Example 24 2-(4-Cyanomethylbenzyl)phenyl β-D-glucopyranoside

2-(4-Cyanomethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosidewas prepared in a similar manner to that described in Reference Example8 using 4-(2-hydroxybenzyl)-phenylacetonitrile instead of methyl4-(2-hydroxybenzyl)-benzoate. Then the title compound was prepared in asimilar manner to that described in Example 2 using2-(4-cyano-methylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of2-(4-methoxycarbonylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹H-NMR (CD₃OD) δ ppm:

3.35-3.55 (4H, m), 3.67 (1H, dd, J=5.3, 12.1 Hz), 3.82 (2H, s), 3.88(1H, dd, J=2.1, 12.1 Hz), 3.99 (1H, d, J=14.9 Hz), 4.12 (1H, d, J=14.9Hz), 4.91 (1H, d, J=7.6 Hz), 6.85-7.00 (1H, m), 7.00-7.10 (1H, m),7.10-7.20 (2H, m), 7.20-7.30 (4H, m)

Example 25 2-(4-Carbamoylbenzyl)phenyl β-D-glucopyranoside

To a suspension of 4-(2-hydroxybenzyl)benzamide (0.063 g) and1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.33 g) in toluene (3 mL)was added boron trifluoride diethyl-ether complex (0.11 mL), and themixture was stirred at room temperature overnight. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: hexane/ethyl acetate=4/1)to give 2-(4-carbamoylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. To a solution of theobtained 2-(4-carbamoylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in methanol (5 mL) was addedsodium methoxide (0.005 g), and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: ethyl acetate/ethanol=5/1) to give2-(4-carbamoylbenzyl)phenyl β-D-glucopyranoside (0.068 g).

¹H-NMR (CD₃OD) δ ppm:

3.30-3.55 (4H, m), 3.68 (1H, dd, J=5.5, 11.9 Hz), 3.88 (1H, dd, J=2.1,11.9 Hz), 4.04 (1H, d, J=14.9 Hz), 4.19 (1H, d, J=14.9 Hz), 4.92 (1H, d,J=7.5 Hz), 6.90-7.00 (1H, m), 7.05-7.15 (1H, m), 7.15-7.20 (2H, m),7.30-7.40 (2H, m), 7.70-7.80 (2H, m)

Example 2≢ 2-[4-(N,N-dimethylamino)benzyl]phenyl β-D-glucopyranoside

To a solution of 2-[4-(N,N-dimethylamino)benzyl]phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (00.10 g) in methanol (2 mL)and tetrahydrofuran (1 mL) was added sodium methoxide (28% methanolsolution, 0.007 mL), and the mixture was stirred at room temperature for70 minutes. The reaction mixture was concentrated under reducedpressure, and the residue was purified by column chromatography onaminopropyl silica gel (eluent: dichloromethane/methanol=8/1) to give2-[4-(N,N-dimethylamino)benzyl]phenyl β-D-glucopyranoside (0.069 g).

¹H-NMR (CD₃OD) δ ppm:

2.85 (6H, s), 3.35-3.55 (4H, m), 3.69 (1H, dd, J=5.2, 12.0 Hz), 3.88(1H, dd, J=1.9, 12.0 Hz), 3.89 (1H, d, J=15.0 Hz), 3.98 (1H, d, J=15.0Hz), 4.90 (1H, d, J=7.6 Hz), 6.65-6.75 (2H, m), 6.85-6.95 (1H, m),7.00-7.05 (1H, m), 7.05-7.10 (2H, m), 7.10-7.15 (2H, m)

Example 27 2-[(4-Benzyloxy)benzyl]phenyl β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inExample 21 using 2-[4-(benzyloxy)benzyl]phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹H-NMR (CD₃OD) δ ppm:

3.35-3.55 (4H, m), 3.69 (1H, dd, J=5.0, 12.0 Hz), 3.88 (1H, dd, J=2.0,12.0 Hz), 3.92 (1H, d, J=14.8 Hz), 4.03 (1H, d, J=14.8 Hz), 4.91 (1H, d,J=7.3 Hz), 5.03 (2H, s), 6.80-6.95 (3H, m), 7.00-7.10 (1H, m), 7.10-7.20(4H, m), 7.25-7.45 (5H, m)

Example 28 2-[4-(2-Hydroxyethyl)benzyl]-5-methoxyphenylβ-D-glucopyranoside

To a solution of5-methoxy-2-{4-[2-(methoxymethyl-oxy)ethyl]benzyl}phenylβ-D-glucopyranoside (0.053 g) in methanol (2.3 mL) was addedp-toluenesulfonic acid monohydrate (0.032 g), and the mixture wasstirred at 50° C. for 3 hours. The reaction mixture was cooled toambient temperature, triethylamine (0.5 mL) was added to the reactionmixture, and the solvent was removed under reduced pressure. The residuewas purified by preparative thin layer chromatography on silica gel(eluent: dichloromethane/methanol=6/1) to give2-[4-(2-hydroxyethyl)benzyl]-5-methoxyphenyl β-D-glucopyranoside (0.023g).

¹H-NMR (CD₃OD) δ ppm:

2.76 (2H, t, J=7.0 Hz), 3.30-3.55 (4H, m), 3.60-3.75 (3H, m), 3.75 (3H,s), 3.87 (1H, d, J=15.0 Hz), 3.89 (1H, dd, J=1.9, 12.2 Hz), 3.99 (1H, d,J=15.0 Hz), 4.85-4.95 (1H, m), 6.50 (1H, dd, J=2.5, 8.3 Hz), 6.78 (1H,d, J=2.5 Hz), 6.94 (1H, d, J=8.3 Hz), 7.05-7.20 (4H, m)

Example 29 5-Amino-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside

To a solution of 5-amino-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.19 g) in methanol (3.5 mL)was added sodium methoxide (28% methanol solution, 0.064 mL), and themixture was stirred at room temperature for 50 minutes. The reactionmixture was concentrated under reduced pressure, and water was added tothe residue. The resulting precipitated crystals were collected byfiltration, washed with water and dried under reduced pressure to give5-amino-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.12 g).

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.7 Hz), 2.57 (2H, q, J=7.7 Hz), 3.30-3.50 (4H, m), 3.69(1H, dd, J=5.4, 12.0 Hz), 3.81 (1H, d, J=15.0 Hz), 3.90 (1H, dd, J=2.1,12.0 Hz), 3.92 (1H, d, J=15.0 Hz), 4.80-4.95 (1H, m), 6.33 (1H, dd,J=2.2, 8.1 Hz), 6.59 (1H, d, J=2.2 Hz), 6.78 (1H, d, J=8.1 Hz),7.00-7.15 (4H, m)

Example 30 2-[4-(3-Hydroxypropyl)benzyl]-3,5-dimethylphenylβ-D-glucopyranoside

To a solution of 2-[4-(3-benzoyloxypropyl)benzyl]-3,5-dimethylphenol(0.72 g) and 1,2,3,4,6-panta-O-acetyl-β-D-glucopyranose (2.3 g) intoluene (7 mL) and dichloromethane (3 mL) was added borontrifluoride-diethyl ether complex (0.73 mL), and the mixture was stirredat room temperature for 10 hours. Ethyl acetate and a saturated aqueoussodium hydrogen carbonate were added to the reaction mixture, and theorganic layer was separated. The organic layer was washed with brine anddried over anhydrous sodium sulfate, and the solvent was removed underreduced pressure. The residue was dissolved in methanol (6 mL) andtetrahydrofuran (4 mL). To the solution was added sodium methoxide (28%methanol solution, 0.19 m), and the mixture was stirred at 30° C. for7.5 hours. Ethyl acetate and water were added to the reaction mixture,and the organic layer was separated. The organic layer was washed withbrine and dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure. The residue was dissolved in methanol(10 mL), sodium methoxide (28% methanol solution, 0.075 mL) was added tothe solution, and the mixture was stirred at 30° C. for 14 hours. Thereaction mixture was purified by column chromatography on silica gel(eluent: dichloromethane/methanol=8/1). The solvent was removed underreduced pressure, diethyl ether was added to the residue, and theresulting precipitates were collected by filtration. The obtained solidwas washed with diethyl ether and dried under reduced pressure to give2-[4-(3-hydroxypropyl)-benzyl]-3,5-dimethylphenyl β-D-glucopyranoside(0.58 g).

¹H-NMR (CD₃OD) δ ppm:

1.70-1.85 (2H, m), 2.13 (3H, s), 2.27 (3H, s), 2.55-2.65 (2H, m),3.30-3.45 (4H, m), 3.45-3.60 (2H, m), 3.68 (1H, dd, J=5.3, 11.9 Hz),3.87 (1H, dd, J=2.3, 11.9 Hz), 3.95 (1H, d, J=15.5 Hz), 4.15 (1H, d,J=15.5 Hz), 4.80-4.90 (1H, m), 6.65-6.70 (1H, m), 6.85-6.95 (1H, m),6.95-7.10 (4H, m)

Example 31 2-[4-(2-Hydroxyethyl)benzyl]-3,5-dimethylphenylβ-D-glucopyranoside

The title compound was prepared in a similar manner to that described inExample 30 using 2-[4-(2-benzoyloxy-ethyl)benzyl]-3,5-dimethylphenolinstead of 2-[4-(3-benzoyloxypropyl)benzyl]-3,5-dimethylphenol.

¹H-NMR (CD₃OD) δ ppm:

2.13 (3H, s), 2.27 (3H, s), 2.74 (2H, t, J=7.0 Hz), 3.30-3.45 (4H, m),3.60-3.75 (3H, m), 3.86 (1H, dd, J=2.3, 11.9 Hz), 3.95 (1H, d, J=15.4Hz), 4.16 (1H, d, J=15.4 Hz), 4.80-4.90 (1H, m), 6.65-6.70 (1H, m),6.85-6.95 (1H, m), 7.00-7.10 (4H, m)

Example 32 2-(4-Ethylbenzyl)-5-methylaminophenyl β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inExample 29 using 2-(4-ethylbenzyl)-5-methyl-aminophenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of5-amino-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6 Hz), 2.73 (3H, s), 3.30-3.55(4H, m), 3.68 (1H, dd, J=5.7, 12.1 Hz), 3.75-4.00 (3H, m), 4.80-4.90(1H, m), 6.25 (1H, dd, J=2.2, 8.2 Hz), 6.51 (1H, d, J=2.2 Hz), 6.81 (1H,d, J=8.2 Hz), 7.00-7.15 (4H, m)

Example 33 5-Carbamoyl-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside

To a solution of 5-carbamoyl-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.13 g) in methanol (3 mL)was added sodium methoxide (28% methanol solution, 0.043 mL), and themixture was stirred at room temperature for 30 minutes. The reactionmixture was purified by column chromatography on benzenesulfonylpropylsilica gel (eluent: methanol). Diethyl ether was added to the obtainedcompound, and the resulting precipitated solid was collected byfiltration and dried under reduced pressure to give5-carbamoyl-2-(4-ethyl-benzyl)phenyl β-D-glucopyranoside (0.079 g).

¹H-NMR (CD₃OD) δ ppm:

1.19 (3H, t, J=7.6 Hz), 2.59 (2H, q, J=7.6 Hz), 3.30-3.60 (4H, m), 3.70(1H, dd, J=7.2, 12.1 Hz), 3.91 (1H, dd, J=2.2, 12.1 Hz), 4.00 (1H, d,J=15.0 Hz), 4.10 (1H, d, J=15.0 Hz), 5.01 (1H, d, J=7.4 Hz), 7.05-7.20(5H, m), 7.44 (1H, dd, J=1.7, 7.9 Hz), 7.64 (1H, d, J=1.7 Hz)

Example 34 2-(4-Ethylbenzyl)-5-(methoxymethyloxy)phenylβ-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 56 using 2-(4-ethyl-benzyl)-5-(methoxymethyloxy)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of5-methoxy-2-{4-[2-(methoxy-methyloxy)ethyl]benzyl}phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹H-NMR (CD₃OD) δ ppm:

1.19 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6 Hz), 3.35-3.55 (7H, m), 3.69(1H, dd, J=5.0, 12.2 Hz), 3.80-3.95 (2H, m), 3.98 (1H, d, J=15.3 Hz),4.80-4.95 (1H, m), 5.05-5.20 (2H, m), 6.61 (1H, dd, J=2.4, 8.4 Hz), 6.89(1H, d, J=2.4 Hz), 6.94 (1H, d, J=8.4 Hz), 7.00-7.20 (4H, m)

Example 35 2-(4-Ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inExample 28 using 2-(4-ethylbenzyl)-5-(methoxymethyloxy)phenylβ-D-glucopyranoside instead of5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenylβ-D-glucopyranoside.

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6 Hz), 3.35-3.55 (4H, m),3.65-3.75 (1H, m), 3.83 (1H, d, J=15.1 Hz), 3.85-3.95 (1H, m), 3.94 (1H,d, J=15.1 Hz), 4.80-4.90 (1H, m), 6.37 (1H, dd, J=2.4, 8.2 Hz), 6.64(1H, d, J=2.4 Hz), 6.84 (1H, d, J=8.2 Hz), 7.00-7.15 (4H, m)

Example 36 2-(4-Ethylbenzyl)-5-(2-hydroxyethyloxy)phenylβ-D-glucopyranoside

To a solution of 5-[2-(benzyloxy)ethyloxy]-2-(4-ethylbenzyl)phenylβ-D-glucopyranoside (0.022 g) in ethanol (1 mL) was added 10%palladium-carbon powder (0.0082 g), and the mixture was stirred under ahydrogen atmosphere at room temperature for 1 hour. An insolublematerial was removed by filtration, and the solvent of the filtrate wasremoved under reduced pressure. The residue was purified by preparativethin layer chromatography on silica gel (eluent:dichloromethane/methanol=6/1) to give2-(4-ethylbenzyl)-5-(2-hydroxy-ethyloxy)phenyl β-D-glucopyranoside(0.013 g).

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6 Hz), 3.30-3.55 (4H, m), 3.68(1H, dd, J=5.5, 12.1 Hz), 3.80-3.95 (4H, m), 3.95-4.05 (3H, m),4.85-4.90 (1H, m), 6.53 (1H, dd, J=2.3, 8.4 Hz), 6.81 (1H, d, J=2.3 Hz),6.93 (1H, d, J=8.4 Hz), 7.00-7.15 (4H, m)

Example 37 2-(4-Methoxybenzyl)-3,5-dimethylphenyl β-D-glucopyranoside

To a suspension of 2-(4-methoxybenzyl)-3,5-dimethyl-phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7.4 g) in ethanol (150 mL)was added 2 mol/L aqueous sodium hydroxide solution (65 mL), and themixture was stirred at room temperature for 2 hours. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine and dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure togive 2-(4-methoxybenzyl)-3,5-dimethylphenyl β-D-glucopyranoside (5.2 g).

¹H-NMR (CD₃OD) δ ppm:

2.13 (3H, s), 2.27 (3H, s), 3.30-3.50 (4H, m), 3.60-3.75 (4H, m),3.80-4.00 (2H, m), 4.00-4.20 (1H, m), 4.80-4.90 (1H, m), 6.60-6.80 (3H,m), 6.85-6.95 (1H, m), 7.00-7.10 (2H, m)

Example 38 5-Cyano-2-(4-methoxybenzyl)phenyl β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inReference Example 74 using 5-cyano-2-(4-methoxybenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of5-methoxy-2-{4-[2-(methoxy-methyloxy)ethyl]benzyl}phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹H-NMR (CD₃OD) δ ppm:

3.30-3.45 (1H, m), 3.45-3.60 (3H, m), 3.69 (1H, dd, J=5.9, 12.2 Hz),3.75 (3H, s), 3.91 (1H, dd, J=2.2, 12.2 Hz), 3.98 (1H, d, J=15.1 Hz),4.07 (1H, d, J=15.1 Hz), 4.99 (1H, d, J=7.4 Hz), 6.75-6.85 (2H, m),7.10-7.20 (2H, m), 7.19 (1H, d, J=7.7 Hz), 7.28 (1H, dd, J=1.4, 7.7 Hz),7.49 (1H, d, J=1.4 Hz)

Example 39 5-Methoxy-2-(4-methoxybenzyl)phenyl β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inExample 29 using 5-methoxy-2-(4-methoxy-benzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of5-amino-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside

¹H-NMR (CD₃OD) δ ppm:

3.30-3.55 (4H, m), 3.68 (1H, dd, J=5.8, 12.0 Hz), 3.74 (3H, s), 3.75(3H, s), 3.80-4.00 (3H, m), 4.80-4.95 (1H, m), 6.50 (1H, dd, J=2.4, 8.4Hz), 6.70-6.85 (3H, m), 6.93 (1H, d, J=8.4 Hz), 7.05-7.20 (2H, m)

Example 40 5-Carbamoylmethyl-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside

The title compound was prepared in a similar manner to that described inExample 33 using 5-carbamoylmethyl-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of5-carbamoyl-2-(4-ethylbenzyl)phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.5 Hz), 2.57 (2H, q, J=7.5 Hz), 3.30-3.55 (6H, m), 3.69(1H, dd, J=5.7, 12.2 Hz), 3.90 (1H, dd, J=2.2, 12.2 Hz), 3.92 (1H, d,J=14.6 Hz), 4.03 (1H, d, J=14.6 Hz), 4.93 (1H, d, J=7.6 Hz), 6.87 (1H,dd, J=1.4, 7.6 Hz), 7.00 (1H, d, J=7.6 Hz), 7.00-7.20 (5H, m)

Example 41 5-[3-(Ethoxycarbonyl)propyloxy]-2-(4-ethylbenzyl)phenylβ-D-glucopyranoside

To a suspension of 2-(4-ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside(0.051 g) and cesium carbonate (0.13 g) in N,N-dimethylformamide (2 mL)was added ethyl 4-bromobutyrate (0.028 mL), and the mixture was stirredat 50° C. for 1 hour. The reaction mixture was cooled to ambienttemperature, water was added to the reaction mixture, and the resultingmixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and the solvent was removed under reducedpressure. The residue was purified by preparative thin layerchromatography on silica gel (eluent: dichloromethane/methanol=9/1) togive 5-[3-(ethoxycarbonyl)propyloxy]-2-(4-ethylbenzyl)phenylβ-D-glucopyranoside (0.028 g).

¹H-NMR (CD₃OD) δ ppm:

1.18 (3H, t, J=7.6 Hz), 1.23 (3H, t, J=7.1 Hz), 1.95-2.10 (2H, m), 2.48(2H, t, J=7.5 Hz), 2.57 (2H, q, J=7.6 Hz), 3.30-3.55 (4H, m), 3.68 (1H,dd, J=5.7, 12.1 Hz), 3.80-4.05 (5H, m), 4.12 (2H, q, J=7.1 Hz), 4.88(1H, d, J=7.4 Hz), 6.49 (1H, dd, J=2.4, 8.8 Hz), 6.77 (1H, d, J=2.4 Hz),6.92 (1H, d, J=8.8 Hz), 7.00-7.15 (4H, m)

Example 42 2-(4-Methoxybenzyl)-5-methoxymethylphenyl β-D-glucopyranoside

To a solution of 2-(4-methoxybenzyl)-5-methoxymethyl-phenyl2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.14 g) in methanol (3 mL)was added sodium methoxide (28% methanol solution, 0.047 mL), and themixture was stirred at room temperature for 3 hours. The reactionmixture was purified by column chromatography on benzenesulfonylpropylsilica gel (eluent: methanol) to give2-(4-methoxybenzyl)-5-methoxymethylphenyl β-D-glucopyranoside (0.084 g).

¹H-NMR (CD₃OD) δ ppm:

3.35 (3H, s), 3.30-3.55 (4H, m), 3.69 (1H, dd, J=5.5, 12.1 Hz), 3.74(3H, s), 3.80-3.95 (2H, m), 4.01 (1H, d, J=15.0 Hz), 4.35-4.45 (2H, m),4.92 (1H, d, J=7.4 Hz), 6.75-6.85 (2H, m), 6.90 (1H, dd, J=1.4, 7.7 Hz),7.02 (1H, d, J=7.7 Hz), 7.10-7.20 (3H, m)

Test Example 1

Assay for Inhibitory Effect on Human SGLT2 Activity

1) Construction of the Plasmid Vector Expressing Human SGLT2

Preparation of the cDNA library for PCR amplification was performed byreverse transcription of a total RNA deprived from human kidney (Origene) with oligo dT as the primer, using SUPERSCRIPT PreamplificationSystem (Gibco-BRL:LIFE TECHNOLOGIES). The DNA fragment coding for humanSGLT2 was amplified by the PCR reaction, in which the human kidney cDNAlibrary described above was used as the template and the following oligonucleotides 0702F and 0712R, presented as Sequence Number 1 and 2respectively, were used as the primers. The amplified DNA fragment wasligated into pCR-Blunt (Invitrogen), a vector for cloning, according tostandard method of the kit. The Escherichia coli HB101 (Toyobo) wastransformed according to usual method and then selection of thetransformants was performed on the LB agar medium containing 50 μg/mL ofkanamycin. After the plasmid DNA was extracted and purified from the oneof the transformants, amplifying of the DNA fragment coding for humanSGLT2 was performed by the PCR reaction, in which the following oligonucleotides 0714F and 0715R, presented as Sequence Number 3 and 4respectively, were used as the primers. The amplified DNA fragment wasdigested with restriction enzymes, Xho I and Hind III, and then purifiedwith Wizard Purification System (Promega). This purified DNA fragmentwas inserted at the corresponding restriction sites of pcDNA3.1 (−)Myc/His-B (Invitrogen), a vector for expressing of fusion protein. TheEscherichia coli HB101 was transformed according to usual method andthen selection of the transformant was performed on the LB agar mediumcontaining 100 μg/mL of ampicillin. After the plasmid DNA was extractedand purified from this transformant, the base sequence of the DNAfragment inserted at the multi-cloning sites of pcDNA3.1 (−) Myc/His-Bwas analyzed. This clone had a single base substitution (ATC which codesfor the isoleucine-433 was substituted by GTC) compared with the humanSGLT2 reported by Wells et al (Am. J. Physiol., Vol. 263, pp. 459-465(1992)). Sequentially, a clone in which valine is substituted for theisoleucine-433 was obtained. This plasmid vector expressing human SGLT2in which the peptide presented as Sequence Number 5 is fused to thecarboxyl terminal alanine residue was designated KL29. Sequence Number 1ATGGAGGAGCACACAGAGGC Sequence Number 2 GGCATAGAAGCCCCAGAGGA SequenceNumber 3 AACCTCGAGATGGAGGAGCACACAGAGGC Sequence Number 4AACAAGCTTGGCATAGAAGCCCCAGAGGA Sequence Number 5KLGPEQKLISEEDLNSAVDHHHHHH2) Preparation of the Cells Expressing Transiently Human SGLT2

KL29, the plasmid coding human SGLT2, was trnasfected into COS-7 cells(RIKEN CELL BANK RCB0539) by electroporation. Electroporation wasperformed with GENE PULSER II (Bio-Rad Laboratories) under thecondition: 0.290 kV, 975 μF, 2×10⁶ cells of COS-7 cell and 20 μg of KL29in 500 μL of OPTI-MEM I medium (Gibco-BRL:LIFE TECHNOLOGIES) in the 0.4cm type cuvette. After the gene transfer, the cells were harvested bycentrifugation and resuspended with OPTI-MEM I medium (1 mL/cuvette). Toeach well in 96-wells plate, 125 μL of this cell suspension was added.After overnight culture at 37° C. under 5% CO₂, 125 μL of DMEM mediumwhich is containing 10% of fetal bovine serum (Sanko Jyunyaku), 100units/mL sodium penicillin G (Gibco-BRL:LIFE TECHNOLOGIES), 100 μg/mLstreptomycin sulfate (Gibco-BRL: LIFE TECHNOLOGIES) was added to eachwell. After a culture until the following day, these cells were used forthe measurement of the inhibitory activity against the uptake ofmethyl-α-D-glucopyranoside.

3) Measurement of the Inhibitory Activity Against the Uptake ofmethyl-α-D-glucopyranoside

After a test compound was dissolved in dimethyl sulfoxide and dilutedwith the uptake buffer (a pH 7.4 buffer containing 140 mM sodiumchloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesiumchloride, 5 mM methyl-α-D-glucopyranoside, 10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid and 5 mMtris(hydroxymethyl)aminomethane), each diluent was used as test samplefor measurement of the inhibitory activity. After removal of the mediumof the COS-7 cells expressing transiently human SGLT2, to each well 200μL of the pretreatment buffer (a pH 7.4 buffer containing 140 mM cholinechloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesiumchloride, 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acidand 5 mM tris(hydroxy-methyl)aminomethane) was added, and the cells wereincubated at 37° C. for 10 minutes. After the pretreatment buffer wasremoved, 200 μL of the same buffer was added again, and the cells wereincubated at 37° C. for 10 minutes. The buffer for measurement wasprepared by adding of 7 μL of methyl-α-D-(U-14C)-glucopyranoside(Amersham Pharmacia Biotech) to 525 μL of the prepared test sample. Forthe control, the buffer for measurement without test compound wasprepared. For estimate of the basal uptake in the absence of testcompound and sodium, the buffer for measurement of the basal uptake,which contains 140 mM choline chloride in place of sodium chloride, wasprepared similarly. After the pretreatment buffer was removed, 75 μL ofeach buffer for measurement was added to each well, the cells wereincubated at 37° C. for 2 hours. After the buffer for measurement wasremoved, 200 μL of the washing buffer (a pH 7.4 buffer containing 140 mMcholine chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mMmagnesium chloride, 10 mM methyl-α-D-glucopyranoside, 10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid and 5 mMtris(hydroxy-methyl)aminomethane) was added to each well and immediatelyremoved. After two additional washing, the cells were solubilized byaddition of 75 μL of 0.2 mol/L sodium hydroxide to each well. After thecell lysates were transferred to the PicoPlate (Packard) and 150 μL ofMicroScint-40 (Packard) was added to each well, the radioactivity wasmeasured with microplate scintillation counter TopCount (Packard). Thedifference in uptake was obtained as 100% value by subtracting theradioactivity in the basal uptake from that in control and then theconcentrations at which 50% of uptake was inhibited (IC₅₀ Value) werecalculated from the concentration-inhibition curve by least squaremethod. The results are shown in the following Table 1. TABLE 1 Testcompound IC₅₀ value (nM) Example 19 120 Example 29 10 Example 30 30Example 31 59 Example 37 290Test Example 2Assay for the Facilitatory Effect on Urinary Glucose Excretion

As experimental animals, overnight fasted SD rats (Japan SLC. Inc.,male, 7 weeks of age, 180-220 g) were used. Ten mg of a test compoundwas suspended or dissolved in 300 μL of ethanol and dissolved by adding1.2 mL of polyethylene glycol 400 and 1.5 mL of saline to prepare a 3.3mg/mL solution. A portion of this solution was diluted with a mixture(saline: polyethylene glycol 400:ethanol=5:4:1) to prepare 3.3, 0.33 and0.33 mg/mL solution. After body weights of the rats were measured, thesolution of test compound was intravenously injected to the tail vein ata dose of 3 mL/kg (10, 1, 0.1 mg/kg). For control, only a mixture(saline:polyethylene glycol 400:ethanol=5:4:1) was intravenouslyinjected to the tail vein at a dose of 3 mL/kg. Immediately afterintravenous injection to the tail vein, 200 g/L of aqueous glucosesolution was orally administered to the rats at a dose of 10 mL/kg (2g/kg). The intravenous injection to the tail vein was performed with 26G injection needle and 1 mL syringe. The oral administration wasperformed with gastric tube for rat and 2.5 mL syringe. The head countin each group was 3. Collection of urine was performed in metabolic cageafter the administration of glucose was finished. The sampling time forcollection of urine was 24 hours after the administration of glucose.After the collection of urine was finished, the urine volume wasrecorded and the urinary glucose concentration was measured. The glucoseconcentration was measured with a kit for laboratory test: GlucoseB-Test WAKO (Wako Pure Chemical Industries, Ltd.). The amount of urinaryglucose excretion during 24 hours per 200 g of body weight wascalculated from the urine volume, urinary glucose concentration and bodyweight. The results are shown in the following Table 2. TABLE 2 Amountof Urinary Glucose Dose Excretion Test compound (mg/kg) (mg/24 hours/200g body weight) Example 37 0.1 15 1 125 10 288Test Example 3Acute Toxicity Test

A mixture (saline:polyethylene glycol 400:ethanol=5:4:1) was added to atest compound to prepare 30 mg/mL solution. As experimental animals, 5week old male ICR mice (CLEA JAPAN, INC. 29-35 g, 5 animals in eachgroup), which were fasted for 4 hours, were used. The above solution wassubcutaneously administered at a dose of 10 mL/kg (300 mg/kg) to theabove experimental animals and then observation for 24 hours wasperformed. The results are shown in the following Table 3. TABLE 3 Testcompound Death number Example 37 0/5

INDUSTRIAL APPLICABILITY

The glucopyranosyloxybenzylbenzene derivatives represented by the abovegeneral formula (I) and pharmaceutically acceptable salts thereof of thepresent invention have an inhibitory activity in human SGLT2 and exertan excellent hypoglycemic effect by excreting glucose in the urinethrough preventing the reabsorption of excess glucose at the kidney.Therefore, the present invention can provide agents for the preventionor treatment of a disease associated with hyperglycemia such asdiabetes, diabetic complication or obesity by comprising as an activeingredient a glucopyranosyloxy-benzylbenzene derivative represented bythe above general formula (I) or a pharmaceutically acceptable saltthereof of the present invention.

In addition, compounds represented by the above general formula (II) ofthe present invention are important as intermediates for preparing thecompounds represented by the above general formula (I) orpharmaceutically acceptable salts thereof, and therefore, the compoundsrepresented by the above general formula (I) and pharmaceuticallyacceptable salts thereof can be readily prepared by way of thesecompounds.

[Sequence Listing Free Text]

-   Sequence Number 1: Synthetic DNA primer-   Sequence Number 2: Synthetic DNA primer-   Sequence Number 3: Synthetic DNA primer-   Sequence Number 4: Synthetic DNA primer-   Sequence Number 5: Peptide fused to the carboxyl terminal alanine    residue of human SGLT2

1-12. (canceled).
 13. A benzylphenol derivative represented by thegeneral formula:

wherein R¹¹ represents a hydrogen atom, a protected hydroxy group, aprotected amino group, a protected mono(lower alkyl)amino group, adi(lower alkyl)amino group, a carbamoyl group, a lower alkyl group, alower alkoxy group, a protected hydroxy(lower alkyl) group, a protectedhydroxy(lower alkoxy) group, a lower alkoxy-substituted (lower alkyl)group, a lower alkoxy-substituted (lower alkoxy) group, acarbamoyl(lower alkyl) group, a lower alkoxycarbonyl-substituted (loweralkyl) group, a lower alkoxycarbonyl-substituted (lower alkoxy) group, acarboxy-(lower alkyl) group or a carboxy(lower alkoxy) group; R¹²represents a hydrogen atom or a lower alkyl group; and R¹³ represents alower alkyl group, a lower alkoxy group, a lower alkylthio group, aprotected hydroxy(lower alkyl) group, a protected hydroxy(lower alkoxy)group, a protected hydroxyl-(lower alkylthio) group, a loweralkoxy-substituted (lower alkyl) group, a lower alkoxy-substituted(lower alkoxy) group, a lower alkoxy-substituted (lower alkylthio)group, a lower alkenyloxy group, an aralkyloxy group, a protectedhydroxy(lower alkenyl) group, a carboxy group, a lower alkoxycarbonylgroup, a cyano group, an aralkyloxy(lower alkyl) group, a cyano(loweralkyl) group, a carbamoyl group, a carbamoyl(lower alkyl) group, anprotected amino group, a protected mono(lower alkyl)amino group, adi(lower alkyl)amino group, a lower alkoxycarbonyl-substituted (loweralkyl) group, a lower alkoxycarbonyl-substituted (lower alkoxy) group, acarboxy(lower alkyl) group or a carboxy(lower alkoxy) group; with theproviso that: 1) R¹³ does not represent a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a protected hydroxy(lower alkyl)group, a protected hydroxy(lower alkoxy) group, a protectedhydroxy(lower alkylthio) group, a lower alkoxy-substituted (lower alkyl)group, a lower alkoxy-substituted (lower alkoxy) group or a loweralkoxy-substituted (lower alkylthio) group when R¹¹ represents ahydrogen atom or a protected hydroxy(lower alkyl) group and R¹²represents a hydrogen atom, and 2) R¹³ does not represent amethyxocarbonylamino group or a cyanomethyl group when R¹¹ and R¹²represent a hydrogen atom, or a salt thereof.